HU230773B1 - Benzamides and related inhibitors of factor xa - Google Patents
Benzamides and related inhibitors of factor xa Download PDFInfo
- Publication number
- HU230773B1 HU230773B1 HU0203289A HUP0203289A HU230773B1 HU 230773 B1 HU230773 B1 HU 230773B1 HU 0203289 A HU0203289 A HU 0203289A HU P0203289 A HUP0203289 A HU P0203289A HU 230773 B1 HU230773 B1 HU 230773B1
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- salt
- compounds
- thrombotic
- compound
- thrombosis
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/40—Y being a hydrogen or a carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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Description
BenKasuidok és rokon X» fater tnhihhobökBenKasuidok and related X »fater tnhihhobok
A találmány új vegyületekre vonatkozik, amelyek hatékony és nagyon szelektív inhibitorai az izolált vagy proh'osnhbtáz komplexszel társított Xa faktornak. Ezek a vegyüietek szelektivitást mutatnak az Xa faktor iránt i ÍS \O< «'«!<. <9\ p ! , ' \ k t ’ )!, h ! !'< t t\ t ,í S ti ti\0 \< \,P> ' '>!<<>!, \ nn uot I k' pé dkl ρΐο,οηηο m» t\> - >,.»< \ d on to t <n ben \ ? ám m, > n, v n< , sopoí <. t o m s o vcgyöietekre, a vegyíkntek gyógyászatit lag elfogadható soha ós gyogyászatilag elfogadható Xászteónyelre Is vonatkozik, amelyek otnlösökben a vérkoagaláetó hatékony és specifikus inhibitoraiként használhatók. A találmány ezen fúhnenően ezekeket: az inhibitorokat etnlösökfeers terápiás szezekliősü slkáímaxő .éljátásökte is vonatkozik olyan heíegségálisspoiök esetében; amelyekre koagnláelös rendellenessegek jelletnxoek.The present invention relates to novel compounds which are potent and highly selective inhibitors of the Factor Xa isolated or associated with the prohlossinase complex. These compounds show selectivity for factor Xa. <9 \ p! , '\ kt') !, h ! ! '<tt \ t, í S ti ti \ 0 \ <\, P>''>!<<> !, \ nn uot I k' pé dkl ρΐο, οηηο m »t \>->,.»< \ d on to t <n ben \? but m,> n, v n <, sopoí <. It also relates to pharmaceutically acceptable, never-pharmaceutically-acceptable xanthene tongues, which are useful as specific and effective inhibitors of blood coagulants. The present invention also relates to the following: inhibitors are also useful in the treatment of ethnicity in therapeutic disorders; which are characterized by coagular disorders.
A hoisosztizis, a vérzős szabályozásá sebészeti eszközhkkei y&gy az érösszebözódás és fcoggniáeié bziolégitti éttiíodooságtsi révéti töbémk, A talslotáoy knltmosen s vér koagnláeipisval foglalkozik, és azokkal a módokkal, amelyekben ez segít: fenntartási az. emlős keringésének integritását sérülés, gytslladús, betegség, kö«geniEö:is betgkt. őisafimkeié vagy más íőisxaksdás után. Noha a yéídénmzkék és a vés? koagnláoiój& egytkánt szerepet játszik á íomlbusképzödősbén, eisosmbnn a kösguláélős kaszkád bizonyos kötnponenset felelősek azoknak a folyamatoknak a iéierősífőséétt vagy meggyorsításáért, amelyek a vérlemezkemggregáeiöhttn é.s fibrin-iemkóöáshsttíészt vesznek.Hoosostasis, the control of hemorrhage with surgical tools, and vascular connectivity and fcoggnialia are boliolegitic nutritional revolutionary myals, Talslotáoy knltmosen s blood coagnláleipis, and the ways in which it helps. mammalian circulatory integrity injury, ulcerative, disease, geniEö: also betgkt. after a snapshot or any other blackout. Although Yiddish blue and chisel? In addition to playing a role in coagulation, the eisosmbnn coagulase cascade is responsible for a certain amount of cytoplasmic activity that accelerates or accelerates platelet aggregation and fibrin production.
A koágtíláclös ksszkádbsé; valamint a. héínoszlázisháb s trotnbin egy kulcsfontosságé ettzltö. A íröínhin központi szerepet játszik a trombózisban azon képessége révén, hogy katalizálja a fibrlnogéo Sbrinnó való átalakulását, és azáltal. hogy hatékony Yárlctnezkc-aktm-áló hatással rettdetkezih. A trosnbm-aktivhás közvetlen vagy közvetett gátlására irányulták az újabb idők arshkoaguhhss stratégián ntnelyekrei Claeson G, ad áttekintés; st 'Aymhetie Eeptkies and Peptidosninmiins as Suhsttstes and Inhibitora of Thromhfn ttod ötber kroteases in. ttte Bksoő Coagnlatloó Systéttf’ cimá eikkéheb íősöob (bog. /bőmmé, b, 41 i-43ö (1994)1. Az gntikoagoiánsok több csoportját használják jelenleg, a klinikai gyakorbíbtíb ti irotbhtn közvetlen vágy közvetett befolyásolására (példám heparínokat, kis meiekalatörnegü heparínokat, heparinszerü vegyületeket ős fcumarinokat).The coagulates in a hot tub; and the. heinous foam and trotnbin made it a key. Iris plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen to Sbrino. that you may have an effective Yárlctnezkc-activating effect. Direct or indirect inhibition of trosnbm-activus has been targeted in recent arshkoaguhhss strategies, such as Claeson G, ad review; st 'Aymhetie Eeptkies and Peptidosninmiins as Suhsttstes and Inhibitor of Thromhfn ttod fiveber croteases in. ttte Bksooo Coagnlatloó Systéttf 'eikkéheb öö íob (bog. / boomé, b, 41 i-43ö (1994) 1) Several classes of gnticoagulants are currently used, the clinical frequency ir irtbhtn direct desire, heparin heparin, compounds (fcumarins).
A protromhiríáz: komplex, amely magában foglalja a .X» faktort (egy szerin proteáz. a X faktor prskurzöíán&k aktivált: formái» és tagja a kaiclumlon-kölö, gatnma-karboxigluíamlit'GIa^tartalmű, K vitamin-tnggőí véfkogghláelős giikopí'ofóirÍ családnak), amely a zimogón protrotnbtnt az aktív prokosgoláns ttomblnná alakion. .A srombudőÍ eltérően, atnely különféle protein szobYzirátokon. valamint egy specifikus receptoron hat, a Xa iakiornak csak egyetlen fiziológiás sznbszfráíja van, nevezetesen a protrombim Mivel egyetlen X& faktor molekula akár 138 tronsbin molekulát is képes generálni lEiodl et al., 7/mmnó. Eev,, 15, 61.7-019 (I979)j, az Xa faktor közvetlen gátlása, mint a ízombinképzödés Inóirekt gátlásának módja, hatékony antikoaguláns stratégia hmm i'mt η t h'lteo',e.o'Z\, hóm. moh a ’.egtutetrk armb ek a \,t NA bvt s’mekuvn vető pm nmem ríhatok lehetnek ót v/mo dláguoáxfikái szerként: vagy terápiás átlagolásra bizonyos trombeíibus rendellenességek esetében, lásd például a WO 94/13693 számon közrebocsátott netnzetközá szabadakéi bejelentést,Prothromyirase: a complex that includes .X »(a serine protease. Factor X precursors < tb > activated: forms < / RTI > and is a member of the calcinyl-clone, gatnam-carboxyglylamitylGlycase, vitamin K-dependent germinogens). ), which transforms the zymogonial protrotnbtnt into the active procoacolant ttombln. Unlike platelets, there are many different types of protein in the genes. as well as acting on a specific receptor, the Xa family has only one physiological synapsis, namely prothrombin. Since a single X factor factor can generate up to 138 tronsbin molecules lEiodl et al., 7 / mmole. Eev ,, 15, 61.7-019 (I979) j, Direct inhibition of factor Xa as a mode of inhibition of taste zombie production, effective anticoagulant strategy hmm i'mt η t h'lteo ', e.o'Z \, honey. moh a '.gututetrk hems a \, t NA bvt s'mekuvn seeding pm nmem may be used as a v / amodeloxaphics: or for therapeutic averaging in certain thromboembolic disorders, see for example WO 94/13693.
A hemstoíeg szervezetekből származó pohpeptióekröl szí közölték, hogy a Xa faktor Igét? haíékmry és speeifíkos inhibitorát. A 4· 588 58? számó amerikai egyesük állarnokheli szíthndakni ieiráshas· a mexikói pióca, a ry/VvívíAí nyálában levő ííenkóágoiáos ákhvbásröl szárnokíak be. Ennek a nyálnak a fő kompoΑ&φ'ζΦη.’ .9044.1-.002/0 MkTEPohpeptios from hemorrhoids have been reported to express the Factor Xa verb? and a specific inhibitor. A 4 · 588 58? a number of American individuals roamed in the cavernous leirashas · they originate from the leeches of the Mexican leech, ry / VivívíA saliva. The main component of this saliva is & φ'ζΦη. '.9044.1-.002 / 0 MkTE
stense Ns.at β, és tnonkatátsai szériái & Xa úkeso gátló pttlipepűd, asz tihíssziáéle (Α7Ί2) ['.íbé Ástsioo Arid fegwee o!' Ántbtasb, a.'FoMt inhibitor ot Paéter Xa Remis a Pepeated internál Fástéttiid'X 7 Nótf étaz, 243. IDldd-1.1)147 (t§§§)). A Xa laktok egy másik .hatékony ás igen specifikus- stsbibílora a kullancs antskoagyláns pepiid (TÁP'}, amelyet egy pnha kaliatiés, a® Ortíítbóforo.? omnóíírn teljes teáiéból végzett tobrtikeiávsii kölörstelteb el, silóid azt Waxotatt L. ás munkatársai letbák (Tick Astileoagtslasd Pepiidé (ΓΛΡ) is a Nevel inhibitor of Siesd Coagplatien Faéíor Xsr, Nóteee, 2éS, 592--590 (!990jfstense Ns.at β, and tnonkatattsai series & Xa úkeso inhibitory pttlipepid, aschishia (Α7Ί2) ['.íbé Ástsioo Arid fegwee o!' Bytbtasb, a.'FoMt Inhibitor ot Peter Xa Remis at Pepeated Inter Fástéttiid'X 7 Notftaz, 243. IDldd-1.1) 147 (t§§§)). Another efficient and highly specific strain of Xa lactose is the tick anti-coagulant peptide (TÁP '), which has been produced by tobrtikelavsii lozenges from the whole tea of pnha calitiser, the ortho-phosphorus. Pepide (ΓΛΡ) is also a Nevel inhibitor of Siesd Coagplatien Faéoror Xsr, Nóteee, 2éS, 592--590 (! 990jf
Olyats :Xa takbsrt gátló vegyületekrOl, amelyek bem nagy, pstbpepdd llpasd Itdssbttosnk, száitést 'beszámol* tak osár, tóbhek között Tklwell R. R. és munkaiam!, “Stradsgjes tor AnlicoaguInSion Wlth Systthelié. Fsntease tsdoéeess \aInieédotv Vwm tt-sensbia ismerne!$” .9Χν.·ν,9\ AW , ts\ yymy.te^.oge>, tórster \, P &.WR· ktaásssd,. ‘‘p-Ásoidstto Eaifeta es Irraversibia Inhibitora of Facin? l.Xts and Xa atsd Tlwásbíts, Xieeöretáííty, 22, W2IM935 (1944); (iliostss Y. ás stsdáksssárssb Óssibbsdtry btlbes of Aévr Sytálsetse Fs-etease bábbihA (9124-975) on tise Cosgoiailon System”, /hnwsaWnW,. is, löd-lét) (1985): Sdsrzébeeher 7. és ttsostkstlársa!, öyrsíketlo láhibiitsrs of Bovioe Fáéin? Xa atal Thrmnbm, Comparison oí Tfeeir Ántleoagoiani EiXesessey, ?'k«wb; Ne?. 54, 345-252 (19491, Xssrs 0. M. és ííitssrkáiársas, Mééisstossét Bstséd haeayowín Isttsihltora tat kiypsia ássd Blood Coágoiatidn Fétissé Frdíéááes: Metv Astttéepgtdafita, FAséíséstsAáyr 2.7, 3547-2557 (IN88); liaitptotassts ,k és .munkatársak “Cosspabsoss óf ihb Abtióoagdisni stáb Asiithmmfemfe Ebbel ofFystihdtte Thrombiű ássd faeiór Xa IstisibikísM, 'Brswó, Böemesl., fö, 221)-2271 1991)),Such as: Xa blocking compounds which are large, pstbpepdd llpasd Itdssbttosn, reported * tlar, amongst Tklwell R.R. and my work !, ”Stradsgjes tor AnlicoaguInSion Wlth Systthelié. Fsntease tsdoéeess \ aInieédotv Vwm tt-sensbia would know! $ ”.9Χν. · Ν, 9 \ AW, ts \ yymy.te ^ .oge>, tórster \, P & .WR · ktaásssd,. '' P-Azidstto Eaifeta es Irraversibia Inhibitora of Facin? Xts and Xa Atsd Tlwásbít, Xieereoretí, 22, W2IM935 (1944); (iliostss Y. and stsdáksssárssb Óssibbsdtry btlbes of Aévr Sytálsetse Fs-etease bábihA (9124-975) on the Tissue Cosgoiailon System ”, / hnwsaWnW,. is, loud-being) (1985): Sdsrzébeeherlsazstirl, 7th ed. Bovioe Fayein? Xa atal Thrmnbm, Comparison oí Tfeeir Ántleoagoiani EiXesessey,? 'K «wb; Not?. 54, 345-252 (19491, Xssrs 0.M. and Lith. Scr., Mééststét, Bsted haeayowin Isttsihltora tat kiypsia dig Blood Coagealid Fetish to Frede: Metv Astttéepgtdafita, INs. ihb Abtióoagdisni Staff Asiithmmfemfe Ebbel ofFystihdtte Thrombiú dig faeiór Xa IstisibikísM, 'Brswó, Böemesl., main, 221) -2271 1991)),
Mások olyast Xa fhkter inhibitorokat Írtak is, tsstselyek kis stselekelsijsi szerves vsgylttelék, példást! elitég-bskaSssimó heterociklusos vegyűietek, amelyek bciyettesbökésts anddsoocsoportot tartalmaznak, ahol & vesytdetek két itsttkesős -esopórtitt. kötísilsei a Xa. óktör két aktív hélyébáz, Á WO 94/25249 szótét stésriáétközi közrelsocsátáss iratban példáid tennináils -OíI-’-XÍ'Ií-XÍÍ·! csoportot étttastoazd psrazol-végydlrteket isstsertebsák; a WO 97/21.427 szésoá éesn&éíkdst köarabeesáhis! iratban bázsktts essspöritai szobszit!t.iák benzhtiidazol-vegydleískét srstek se, tsstsely feá-zikns csoport sgy «ai^ltwporfho-x egyestes vagy elstpzö láncé. alkilén-, <WÖ> 11 ,t », O e -. t o v\<pe itr, \ o\ a -1 \νι o m W<)' sóst \ ws ks ιΆμ'Όμ i , élysiíi végybletákrs vonatkozik, -amelyekben' 49b»i'lM-aikllam1diao^ipeAdtn<· és d-lésissvÍ-X-alIrisassldsso·pipes4dlís<syms>rt egy karhexamidalkiiénantino-hidon át kapcsolódik egy 3rtimidltx>featlcs«perihoz; és az kp 09205 s<\0tiu «.megás szobudalms ienrtran óban ttgssslek'k? osnersetnek, suoebakbesi ept antOtsto>'ulist,,<.potlito' eev 4 leuevs \ ók kitsüdsí'op'pefOssuímpest henetse.MCtt mgs hehenvsW'tkm szsstk'suéüovagy kiss'bosisstssd áthidaló csoporton kérésztől kapcsolódik.Others have also written Xa fhkter inhibitors, tsstselys small stselekelsijsi organic food, exemplary! elite-bskaSssimo heterocyclic compounds containing a bciyettesbökés anddsoo group, where " Xil. two active footbases, for example, in WO 94/25249 Interstellar Intermediate Publication, are examples of ternary-O-I-X-I-X-I! a group of dietary-enriched psrazole endpoints; WO 97/21427 is a sharp and sharp stone carabee! in Espooite, the benzhydrazole chemical chain is not a single chain or an elongated chain of a carbonyl group. alkylene-, <W0> 11, t », O e -. tov \ <pe itr, \ o \ a -1 \ νι om W <) 'salt \ ws ks ιΆμ'Όμ i, illysiil endplates apply, in which' 49b »i'lM-aikllam1diao ^ ipeAdtn <· and d-lésissvi -X-alIrisassldsso · pipes4dlís <syms> rt is linked to a 3rtimidltx> featlcs «peri via a karhexamidalalkylene antinoid; and kp 09205 s <\ 0tiu «.mother roomudalms in innrtran ttgssslek? osnersetnek, suoebakbesi ept antOtsto> 'ulist ,, <. potlito' eev 4 leuevs \ ók kitsüdsí'op'pefOssuímpest henetse.MCtt mgs hehenvsW'tkm szsstk'suéüovov or kiss'bosisstssd joined by a bridgehead.
Festtsál! az igésty a hetsitssszlázls szssbályozására és a irPtstbsnképzitdbs bs az étretídsserben a isissrsbb álsstl tssdsÁíbt teás patológiás isslystetabík, Így a teszletiiiíís és & gytsliadés istegeidzésére és kezelésbre aíkstlsnas bstékíttsy terápiás szerek iráet. Közeiepbról istvsábbst! t$ iestísál! az igény olyast vegyűietek irástt. antelyek a Xa Okirat vagy astststk preknezotait szesekiiyes) gátolják. Olvass vevőietekre van .szükség, amelyek a már Xtssétiekidl eltérő átltidsid és ítistkeós esoptbi-kOéthreáciéksi tarhdétserésk, kstiöádsers Olyast vcgylleípkre, amelyek szdgkilven vagy elsósofban « Xa íáklstrhöz köiOdstek. Olyast vegyűietek kivásttstesaio amelyek nagyobb tstésiékbest kdtédssek a X& lakiéihoz, tstias a srootbisthitz, kdldstösséss olvastok, amelyeknek jsá & biológiai használhatósága éóvazy old'hatósága.Festtsál! the verb to regulate herbal scabies and the irPtstbsn picturezitdbs bs in the diet regimen include the pathological isslystetab of the isissrsbb cisdsAbt tea, thus improving the treatment and treatment of heredity. From the middle of the box! t $ get in! the need for such chemicals is writing. antelas inhibit the X-ray or astststk precnezotes (seiciiyes). There is a need for readers who have a variety of ophthalmic and ophthalmic esoptbi kits that are different from Xtssétiekid, kstiöádsers Such vcgylleípks, which are tied to or in the first place. Compounds that have a higher feed content for X & ls, are srootbisthitz, kdldstos and read, which have a biological solubility and bioavailability.
A találntány összefoglalásaSummary of the ingenious
Á iáláipiáíiy g Xa lakttytt gáijö ól vépyltletéksy, á vegybleiek gyögyásztítilág elíögtsdháSó izotnerjéire, éói·· ro, U'd'rfttt.t, s.'nhmtn >,- es tk-oegtv ''' ' «f'., 'ks.t s tektjmr ,t unjvau'0 gyozs ts.sttks;.A l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l e d t y t h e t-oegtv '.' .ts tektjmr, t unjvau'0 gyozs ts.sttks;.
elfogadható- készhutényekte vonafkosik, amelyek speciális biológiai íuisjóortságóak és taalésökbert a vérkoagtdáció hatékony és specifikus trthibitöralkértt használhatók. A Találmány ezen lühihitorokat diagttoszltkai reagensekként vagy erahisokbett olyan betegségál lapotok terápiás szereként alkalmazó eljárásokta, amely betegsslgál laputokat nénikIvánaus» trombózis jeilomzó, vagy amelyeknél koagokielós rendellenességek fordulnak ele, igy bármilyen trontbo/is aktsl kozveotat akta smkos/oroét 'vagy cerobrovaszkulátls síindttana, a vénás érrendszerben jelentkező bármilyen trombóztsos szindróma, bármilyen koagulopátia, és bármilyen trotnbózisos szövődmény kezelésére alkalmas eljárásra, atneiy testen kívüli keringéssel vagy műszerezéssel társul, és biológiai iútí?iákh;ö! köágöláctö gáilásáís. ál kabnas eljárásra is vonatköstk,acceptable, ready-to-eat fries, which are special biological lichen and can be used as an effective and specific trthibital fungus for blood coagulation. The present invention provides methods for using these short monitors as diagnostic reagents or as a therapeutic agent of erahisokbet in the treatment of diseases of the sclera which have a tenderness in patients with lymphoma, lymphoma, or in which coagulogastric disorders occur, such as any thrombotic syndrome, any coagulopathy, and any method for treating trotnose complications, bringing about extracorporeal circulation or instrumentation, and biological iutathias; in the control of locust beans. we also train for a false cabal,
Bizóbyös megvalósítói» módökbótt á találmány tárgyai ói vegyttiatek képezik, amélyek hatekótty és nagyon szolekliv inhibitorai az izolált Xa faktornak, sasikor protrotnhináz komplexbe vart foglalva, fizok a vegyültök -z'lakút ,tw ut itatnak »v \t taktus uanr t ke.sgul.u'Os k.t.-zknd \ ig\ a filnroolatkn kisüsd más 1« pteuz.ut ,d tpéklütü ,t m>niht5«i3if eik-ontteu. os mugno-^íüru u,5e,ensekl>eot tnlammt trombózis Peru. s szerekként alkalmazhatók.In some embodiments, the subject matter of the present invention is very chemical, deep inhibitors and highly soluble inhibitors of the isolated Factor Xa, encapsulated in a protrothininase complex, and I pay the compound-z'lakut, tw path drink uanr t ke.sg. u'Os kt-zknd \ ig \ a filnroolatkn kisysd other 1 «pteuz.ut, d tpéklütü, tm> niht5« i3if eik-ontteu. os mugno- ^ ture u, 5e, ensekl> eot tnlammt thrombosis in Peru. s as agents.
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vagy ennek gyógyszerószetlleg elfogadható sójára vonatkozik, abc? 4 képletekbenor does it refer to a pharmaceutically acceptable salt thereof, alphabetically? 4 formulas
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NHNH
Y'O».,, jelentése a következő esoponhől vas kiválasztva: -F, ··€:. Xs\ -051 -CH, és -0CH?,Y'O ». ,, meaning from esopon iron selected: -F, ·· € :. Xs \ -051 -CH and -0CH ? .
Λ találmány kiterjed gyógyászati készdaiányekre, ípnoiyek egy ΙόΟοΒον szeried vegyitíeí győgyásxáiilág hatékony mennyiségét gyógyászatiiag elfogadható hordozóval együtt tartalmazzák és emlősök nemklvánt treanV! XX i x , ' Χί, ? ΊΧ (ih O i-'Xxfx < ( 1 t/xl'SU Yí χ i! oThe invention encompasses pharmaceutical formulations comprising an effective amount of a therapeutic compound of the invention in combination with a pharmaceutically acceptable carrier and a mammalian non-intravenous treanV! XX i x, 'Χί ,? ΊΧ {ih O i-'Xxfx <(1 t / xl'SU Yí χ i! O
A találmány kifogod továbbá s fofosíkifoi alkahbazásokra:: s találmány szarihd vepviriGek a!fosris>azáss mem-kivánt trombózisai jellfobzob álbsmb kegbéséfo alkalmas gyógyszer ofoáribásü, és a találmány szerinti vegyületek alkalmazása Melóglai minták koagulációjának fodlásábi alkalmas gyógyszer siődribásá,The invention further relates to the use of the compounds of the invention for the treatment of coagulation of melophageal specimens, and to the use of the compounds of the invention for the prevention of thrombosis of the sarcophagus.
A iuküuOu', nnábh» <>5\á« mwn.Aím! foszlmsenyekre ^ouatfo-rik, rtsofookgg tafobanm «tissi» a· gyület gyézyóöímsfog bofokirtsv mennyiséget kb-foírssszz-éi; gyógyászsfodg sílfogadbbió böíüöxőv&i ^ütt. A találmány szSíriíbl és köíAÍHiényak: sKÜösökhen olyan. boíiígsásállopoSök: megelőzésére vsgy kezeiéV x x fo'» M\ l\ X , » 'b'tx<\ x' '\ fo * '<Ί\' ' XX Ox< \x' 'Sx >'\ \'h Ρ’ΛΙ A X- ' ' xxS<px fol-borlk, n^nbbá aifobnasal, sárolt foSKrssekekbtn 1? nnmakbasi a kx\sysj!a<'io irtegrioréfofo. A Ιηΐ,ώη,ιηγ szorisfo gyépvászori készítményt adott esetheti további terápiás szerekkel, így teombózlseilenes ős/v&gy «temberiilkas ás/vagy soriikoagpláns szerekkel kosssbisfocsóbass adagoljuk.The iuküuOu ', nnábh »<> 5 \ á« mwn.Aím! for fossils, ouatfoic rik, rtsofookgg tafobanm «tissi» is the amount of ca. healing racket slippers bouncers & hitting. DETAILED DESCRIPTION OF THE INVENTION [0002] The present invention is related to Syria and other deficiencies. Boolean Healing States: Preventing Vs. xx fo '»M \ l \ X,»' b'tx <\ x '' \ fo * '<Ί \' 'XX Ox <\ x' 'Sx>' \ \ 'h Ρ' ΛΙ The X- '' xxS <px fol-borlk, n ^ nbbá aifobnasal, cured foSKrssekekbtn 1? nnmakbasi a kx \ sysj! a <'io irtegrioréfofo. The sorghum composition Ιηΐ, ώη, ιηγ may be administered with additional therapeutic agents, such as antispasmodic ancillary / orthelmintic and / or serial coagulant agents.
A miálnifog részletes bmeéekseA detailed bmeéek of the miálnifog
A jelen találmánnyal. és íesVássat összhangban a következb fogaknak fofonfoss az siébbískbssrt megadott, amennyiben nincs snáskóppen meghatározva.With the present invention. and, in accordance with the following teeth, fofonfoss has provided the horns, unless otherwise specified.
Az mik!lesöpört telített alslás ésöposdsskbi: jelent, amelyek egyértés vágy elágazó lábcó vogy gyfoós csoportok -lehetnek,What is swept saturated sleep and epiphyses: mean, which may be a clear desire for branched foot or gypsy groups,
Λ ínekléssesispoíS 4:11,- csoporté* jelessíÍn Singing Displacement 4:11, - Group * Significant
A „gyöiyYiiszebibg elfogadható sok' meghaturstzás a vegyületek sóira atal, amelyek egy vegyölet és egy .,,-eisbs veg> sze?mién s&\ lmeil>ieacn>p>\\stanoaebak.. írek e \egs ölesek mind szabad bans. nnoü setorosában használhatók, A gyakorlatba;* a só forma, alkalmazása megfelel a. bázis forma ssikabrtazáforssk; snhsd a savaddlelós-, .mssd.a bázisaddleiőa sók a jeless táláimány' körébe risrfozmsk.The "gyrate tolerable many" additions to the salts of the compounds, which are a compound and a., - eisbs veg> s s \\ lmeil> ieacn> p> \\ stanoaebak .. are written all free bans. nnoü setorosos, In practice, * the salt form, the application corresponds to the. base form ssikabrtazáforssk; snhsd the acid addition, .mssd.the base addition salts to the renowned platter 'risrfozmsk.
A gyógyászatilag elfogadható ssvsdóiciós só” srseghalározáa olyan sókra atal, amelyek a szabad bázisok biológiai hatókssnysságát és tulajdonságait megtartják, és. amelyek, sem biológiailag, setn más módon nem nemkívánatosak,. és amelyeket szervetlen savakkal, példáéi hidfosgén-klornldaí, hid«>gén-brosnkldal,· kénsavval, szlésrostosáéval,. foszlós sísyvzI, és szerves ssávákkal, példáéi éeetsavvál, propionsavval, glskolsavval., pkisszólbsavvbb b::<fi.!sbvvíii, •tnaleiasavvaí, malonsawel, ítet'ostyáakősavs'al, fomámavval, borkőaavvml, cltromsavvaí, beozosfosvvak fohójsavvaí, mandalasavwt, nsetánszalfonssrvval, etánszöífonsavvai, p4trioölsz«ifoxs8av'val vagy szidicilsiisvai éilikib.!; elé.The pharmacologically acceptable ssvddation salt is characterized by salts which retain the biological activity and properties of the free bases, and. which are not otherwise undesirable, either biologically or otherwise. and with inorganic acids, such as hydphosgene chloride, hydro genes, sulfuric acid, styrofoam. sísyvzI sleazy and organic ssávákkal, for example, Acetic acid, propionic acid, glskolsavval. pkisszólbsavvbb b :: <fi.! sbvvíii, • tnaleiasavvaí, malonic, ítet'ostyáakősavs'al, fomámavval, borkőaavvml, cltromsavvaí, beozosfosvvak fohójsavvaí, mandalasavwt, nsetánszalfonssrvval, etánszöífonsavvai , p4triool with «ifoxs8av» or sidicilsiisva ililib! edge.
A ^gyógyászatilag eílngadható házisaddíciós: aók‘* meghatározás azekna a sókra' ssfok amelyek szervetlen bázisokból saármaztailastők, i lyebek a nátrium-, kálinm-, bíbort-, anortónintn», kalcium-, magnérinm··, vas-,. elnkréz-, mangárn és az ahanhthmsssók. Kölőnösen. előnyösek sz ammónkssn», kálium-·,. ssáfodbS'·, fosfosfod-· ős a sbsgisébbsíösós., Gyógyászatilag elfogadható szerves nem-toxlkns bázisokból származtatott- sók többek között a primer, szekander és tercier asninefcből, helyettesített, ezen beid! a természetben elófordalő belyettesheh aminokbőí, .györöa amisekből és hárikw ioncserélő gyantákból levezethető sók, ilyen példást az Ιζορίορΐνηηοη, ií'brtét 1 irtibs fo, dieil I -amin, öfod i-ssbib, ísápröp ll-bbs t?r, etanol -me is, 2-dfobimb in.e-etaoel, írimelamio, dfoikfoheallxamln, bzbrt arghtlts, bAyskibs, koriéi», profod», hidra-baamp. foss!», hetahp ertléis-dismiirt gtákozssrtbs, meiíiglökantm, teebromin, parin, piperazin, pipekdb*, N-edlpí.periidsi és egy mslisrbfogysnbss. -sója. Olőaósen előnyös szerves sem-tonikss bázis az ízoporiéhartsbb s dieilfoamlb, az etsookmnin,«irkeeietntm b dteikióhexihatnin, a kőrist és a kssribbs..The pharmaceutically acceptable home additions: the definition of azec is the salt derived from inorganic bases, including sodium, potassium, peach, anortone, calcium, magnesium, iron. manganese and ahanhthmsss salts. In particular in view. preferred are ammonium, potassium,. ssafodbS '·, phospho - phosphate salt, s., salts derived from pharmaceutically acceptable organic non - toxinic bases, including primary, secondary and tertiary asninefc, substituted with these beid! salts derived from naturally occurring belyettesheh amines; , 2-dfobimb in.e-etaoel, iriramelamio, dfoikfoheallxamln, bzbrt arghtlts, bAyskibs, koriéi », profod», hydra-baamp. foss! », hetahp ertléis-dismiir gtaakozssrtbs, meiglökantm, teeromin, parin, piperazine, pipekdb *, N-edlpí.periidsi and one mslisrbfogysnbss. salt thereof. Particularly preferred organic semitonic bases are flavored resin, diethookmnin, irkeeietntm b dteixohexihatnin, ash and kssribbs.
öShe
A biológiai toiajdonság a jelen leírást tekintve /« wve eirektor vagy antigén iimkciót vagy olyan aktiCtást jelent, amelyet egy ialáiiJÁy szérűéi vegyüiet közvetlen vagy közvetett tnötlőa kíiéjt, és amelyet gyakran Öt Ή oo\b a b »’ ό uτ t -.t·,' o . A \ CA <.p , e ' a nős; - í,;> <,·>; aa \ enzim-aktivitás vagy enztm-snodttlálö aktivitás, bármilyen hordozőskőtó aktivitás, bármilyen hormonális aktivitás, bármilyen. aktivitás, amely a sejteknek egy evttaeei lel árts mátrixhoz vagy seitfelöleii -mélekólákboz való !tg3j>v\.n ek'.'#ih \ tg'· g.aeha hamn'',, o \n \.<!νο kongna n.nkuo toöbek iox'it ess·. <pt«v>' \\'t\ m fgv s !·> e.e.tlete. s «κ \ o \ > mene , 3 \>on ,< estehk k tnltlntanv szenno rémületekben azok a szénatomok, antebek negs non» azonos hekenedto csoportbe. k,g\ ·,< A,·-in fi, 3\ avaistiΐΛ\<ό . '<j\ > r.glel'ioeo se-rék1 sk ömso ncoi oo\-ok sarat onvmk ra's ezek elegyes Algában létezhetnek. Az ki leírt szintézisekhez racemátókat, enamiemereket vagy dlaszteoeoojereket használhatunk ki Indulási anyagként vagy közbenső tenoékhént. Az ilyen szintézisek eredtéényékén; kapott siéisztereon-sr termékeket Ltomajogfáhás vagy kristályosítás! eljárásokkal vagy a szakterületen Ismert más módszerekkel elválaszthatjuk. Azenantiomer termék-keverékeket a óiasztereoszomerekbez hasonlóan vagy a ;;zakteréieíen lantért, más eljárásokkal szintén széiválasztijsijak. A találmány szerinti vegynietekbsn mindegyik: asziéttéélriás szénatom, amennyiben jelen van, R- vagy S'lkonügnráctéjá lehet, és ezek mindegyike a 'Jalanns ROmbc tarovskBiological property, as used herein, refers to the expression of a direct vector or antigen, or an activity that is directly or indirectly released by a parent compound, and is often found to be "5" or "b". . A \ CA <.p, e 'is married; - í,;><,·>; aa enzyme activity or enzyme activity, any carrier stone activity, any hormonal activity, any. activity that is used by cells to evacuate a matrix or seitfelöleii -molecules! tg3j> v \ .n ek '.'# ih \ tg '· g.aeha hamn''o \ n \. <! νο conna n .nkuo toöbek iox'it ess ·. <pt «v>'\\' t \ m fgv s! ·> eetlete. s «κ \ o \> mene, 3 \> on, <estehk k tnltlntanv in the horror of those carbon atoms, antebek negs non» into the same hekenedto group. k, g \ ·, <A, · -in fi, 3 \ openΐΛ \ <ό. '<j \>r.glel'ioeo series 1 sk ömso ncoi oo \ s sarat onvmk ra's these may exist in mixed Alga. For the syntheses described, racemates, enamemers, or dlasteoeoojers can be used as starting materials or as intermediate tenoes. As a result of such syntheses; obtained sherestone-sr products from lime yoghurt or crystallization! methods or other methods known in the art. Mixtures of asenantiomeric products, similarly to or uncharacterized by the old stereoisomers, are also separated by other methods. Each of the compounds of the present invention may be: an asethelium carbon atom, if present, may be an R or S carbon atom, and each of them is a 'Jalanns ROmbc tarovsk
Előnyős Rivliélí alakokPreferred Rivlielí shapes
A találmány egy előnyös megvalósítási módja: sz alábbi szerko^eh kepletn vsgyliíefreA preferred embodiment of the present invention is the following structure
vagy ennek gyögyszeföszetileg eliöga-áható sójára vonatkozik, aholor its radiolabeled saline, wherein
P. :S jelentése a következő csoportból van kiválasztva:P .: S meaning is selected from the following group:
II. -B -t 1 és -ftr;II. -B -t 1 and -ftr;
R.,s jelentése a következő csoportból van kiválasztva:R. , s meaning is selected from the following group:
F, -Cb -Br. ÁXÍ-ío -Öl i és -CBg ésF, -Cb -Br. ÁXÍ-ío -Il i and -CBg and
A-Q jelentésé a következő esopórtbóil van kiválasztva:The A-Q report is selected from the following esophores:
A í'«Kíh»;i»y egy további elönyö·· megvalóskihi nrödjg egy. a kővetkező <:ί;ορ«!··'<;ό; kiválasztott vegyületre vonatkozik:Another advantage of í '«Kíh»; i »y is · · megvalóskihi nrödjg one. the following <: ί; ορ «! ·· '<; ό; applies to the selected compound:
N-(5'brón)-2-plridinil}-(2-(4-antidinofe»Hkarboníl}an)ino)-fet!ÍikarboxaR5iá«N- (5'brón) -2-plridinil} - (2- (4-antidinofe »} Hkarboníl an) amino) -tetrahydro ÍikarboxaR5iá«!
N-(5 -feróni-S-píi idhnrí-Ce-fő-íiJ-byikkizo.Uniisfenilkaíboíioíanbno}- fetblkarboxantKiN- (5-ferrone-S-Pyridine-Ce-pentyl) -bicyclo-unisphenylcarboxylate} -
K-x5-hrvnt l'nindtrsit-tl'vt-ántidinoíennkaí'bi'ínulaíninolv-nuooteosikarivxanttő,K-x5-hrvnt l'nindtrsit-tl'vt-anantidino-lingin-bi-linin-linol-lingine-carotene,
N-(5-bróín-2-piri<l!t:si)-t 2-(4-( 1 -nietit?. ΐπϋκΐηζοίίη-2-bsfeaiHiaibtsnii í&inlitoy-S-tkiOíofos'ííliíÍtrboxainid, N'C$-kk)r(2-pindii>>(S-ntetöxS'2-U4-(b!O«t5í{2-im5Őaz0Íin-2~5Í>}feni?j-k&rbonÉian)i?50|fe55Íf}karfeoxan5Íd,N- (5-bromo-2-pyrroloethyl) -t 2- (4- (1-nitrito. Ϊ́πϋκΐηζοίίη-2-bsfeaiHiaibtsnii & inlitoy-S-tkiOiofos'yliltrboxainid, N'C $ -kk). r (pyridin-2 >> (S-U4- ntetöxS'2 (b O «{2-t5í im5Őaz0Íin-2 ~ 5t> phenyl} j-k & rbonÉian) 50 i |?? fe55Íf karfeoxan5Íd},
4-(N - (2-(14 -(5-k ;ór( 2-pb'idl f} jkarhstaoti )-;i-tsetosi &nli) katbatmi l)benzöl-karhoxan?ídK4- (N - (2- (14 - (5-k; h (2-pb'idl f) yarhstaoti) ; - i -sethososi n) catbatmi l) benzene carhoxan?
N-(5'klór(z-pb'i<bnX2-'( (44««f«^ín«tjSaminojn5etll}teii)kátbo{h)ao)ino)-5-nietox5f«ntl)karbox3nnd> N-(5«klórt2“piridll)X2-{(4-(imin0pin»hSlalteeiit)fc8lljkasibonlla?«}8o|'‘5-t«etoxlfeny}ka54>oxasniá>.N- (5'chloro (z-pb'i <bnX2 - '((44 «« f «^ tin« tjSaminojn5etll} teii) kbo (h) ao) ino) -5-nethox5f «ntl) carbox3nnd> N- ( 5 «klórt2" pyridyl) X 2 - {(4- (imin0pin »hSlalteeiit) bonlla fc8lljkas i«}? 8o | '' 5-t «} etoxlfeny ka54>oxasniá>.
\-í üti 2- pn tdti !\2-l 14 '(«nífiopqvrsóítao t 4 tf< nil )Lt> ho; olaa ono1 ^-nx to\ doni >ka> bot nnat,\ -í üti 2- pn tdti! \ 2-l 14 '(«nífiopqvrsóítao t 4 tf <nil) Lt> ho; olaa ono1 ^ -nx to \ doni> ka> bot nnat,
N-(5-klót(2'piriőtb)(2-H4-(iríbíioíno?(bb;s'4-i|Íneííi)(b!ánk»rbo?íibirn!íh-S-aíeto.Ki5«íni)k:srlxíxaoí5d,N- (5-satin (2'piriőtb) (2-H4 (iríbíioíno (bb;?!?! S'4, i | Íneííi) (b ank »RBO íibirn iH-S-aíeto.Ki5« INI) k : srlxíxaoí5d,
4-^-(2-(^-15 4ηυ?ην?-ρη idő tlkaíbantoni-f tnetoXík’niiJkvsrbntnnhbeozolkarhoxantRkn Ν·'(5'0··όηϊ(2-ρϊίΊ0ϋ})(2'( (44!ntttK>(t!?e;ilat5yhK)}tofötii)íeníl}körboníiaft5Íi!<í}-$--i!iatoxs:ffit!i'ljktií'b<íS.sií»i<b (2-í S4'(t.úim«'tiMnan<Oin?H!onirtit]k>niSlkarboniktÍninot-5'nj«to\i}entl|-N't5'brbíni2-piríJul'>kafbovamid t\-O inuatp'-p-! )08142-((1 tt5n«(Op)nohó)t)8nnmiHeonjkaíh'H«itunaoh5'inck>Mieíuilk,«hv\a»»)8, N-(5-bróm(2~ph'i<bi}}i2-((4-t Hninopipentiíbwtii tfswtjfcathötsianHBö ; ö-meioxifeílOkazboxítmkb Ν''(0-(?!'όίο(2-ρί!'ί<Η}}!2-((4?!ίοΙοοοκ>?·(«ΐ!ί5-4'ί1«!«ίΗ1Γ«!ίϋ]1·;ί!ί·(5θθί1ί!ίθίηον·5-ο·!«ίοκί1·«ϊ!ϋΑϋΓΐ>οχϋ5Ώκ1? 2-(4-({4-{(dí.8)eH)sanino)iotinoa)et)yiéoil(katboaila)n8Ufl-3-(N-(54dós-(2-pirid5Í))kas1jan)on'(feaox08cstsavés 4-(N'-í2'-(N'(J!-k;ö;42-p;riő5Í!)k<srbi55ísoslb4-b!Ő5'os;f«5i5Íibó5b;50)05l)-be!sZO;k;nfeíjsási)i:íb!:í; vttgy epnek gyógyszereszeoke ef fogyható sója,4 - ^ - {2 - {^ - 15 4ηυ? Ην? -Ρη time tlkaíbantoni-f tnetoXík'niiJkvsrbntnnhbeozolkarhoxantRkn Ν · '{5'0 ·· όηϊ (2-ρϊίΊ0ϋ}) {2' {(44! NtttK> ( t!? e; ilat5yhK)} tofötii) íeníl} Körboníiaft5Íi! <í} - $ - i! iatoxs: ffit! i'ljktií'b <íS.sií »i <b (2-í S4 '{t.úim «'TiMnan <Oin? H! Onirtit] k > niSlcarboniktÍninot-5'nj« to \ i} entl | -N't5'brbíni2-piríJul'> kafbovamid t \ -O inuatp'-p-!) 08142 - (( 1 tt5n «(Op) nohó) t) 8nnmiHeonjkaíh'H« itunaoh5'inck> Mieíuilk, «hv \ a» ») 8, N- {5-bromo (2 ~ ph'i <bi}} i2 - {(4 -t Hninopipentiíbwtii tfswtjfcathötsianHBö; ö-meioxifeílOkazboxítmkb Ν '' {0 - (?! 'όίο (2-ρί!' ί <Η}}! 2 - {(4?! ίοΙοοοκ)> · («ΐ! ί) ί1 «!« ίΗ1Γ «! ίϋ] 1 ·; ί! ί · (5θθί1ί! ίθίηον · 5-ο ·!« ίοκί1 · «ϊ! ϋΑϋΓΐ> οχϋ5Ώκ1 ? 2- {4 - {{dí.8 ) (H) sanino) (iota) (y) oyl (cathoyl) n8 Flu-3- (N- (54-dos- (2-pyrid5))) (cyano) is' (feaoxo) acid 4- (N'-2 '- (N');-;-; - 42 - (p) - (-) - - - - - - - - - - - , - - - - - - - - - - - - - - - ---BIT- edible salt of yoghurt monohydrate,
A tíssabttátty egy meg dönen^'bb twgvalősWt módja a következő csoportból kiválasztott vegybieb-s vonatkozik:One more decisive way to get a tatababttátty is a vegybieb selected from the following group:
AOO 'g ö x-í'us.AOO 'g ö x-í'u s .
οχ, . Αώο <ρ·οχ,. Αώο <ρ ·
ΚίΑκ ί·-···!;ΚίΑκ ί · - ··· !;
i Λ 'νγ-Άίί·' ΗίΆΆ .-•••χ..i Λ 'νγ-Άίί ·' Ηί ΆΆ .- ••• χ ..
^Αχ-.··'·'<^ Αχ-. ·· '·' <
\ « \<.'-'κχ s,>*x.\ «\ <.'- ' κ χ s ,> * x.
Ν >*·' Λ\ ''χΟ-'A\ Vjí Sp''Αγ·'''·^ <··0».Α,0 Dö .0.,0 <xy «LxΝ> * · 'Λ \''χΟ-'A \ V jí Sp''Αγ ·''' · ^ <·· 0 ».Α, 0 D ö .0., 0 <xy« Lx
8?8?
vagy ennek gyógyszerésze·Heg. e Hbgadkaíá sója.or a pharmacist · Scar. e Hbgadkaíá salt.
á íalsteiáísy egy meg «lönyösébb megváiösódsi módja .a kövédiözó csoportból klysiasztötf végyöletí'C yö !\íi\O. \a more lucrative way to survive. from the defending group klysiasztötf the final night! \ íi \ O. \
vagy ennek gyógyszeíbszebísg ebbgsdhaíó sója, .A Ssláim<my égy még siösyösebb Kiégvatósdas! módja a következő e&opörtból kiválasztott vegyakme vo nátkötdk:or its curative salt of ebbgsdhao. way to select the chemical from the following e & opört:
ZNZN
VAVA
V. -' Ss.V. - 'Ss.
rírí
,.·< & S / ' N \.....i,. · <& S / 'N \ ..... i
NR 'SfA , < .A .?NR 'SfA, <.A.?
AHAH
U«\U "\
LRLR
A\THE\
V./ <O·· X .·V. / <O ·· X. ·
V ? V ?
Vj VK ti z /V^sS-V.Nt'í:Vj VK ti z /V^sS-V.Nt'í:
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A találmány égy íség eíósyösehfe siegvskssm.sl módja a követted csQportból kíválasaSött vemydlest vó«átkozik:The Invention of the Invention The method of selecting a follow-up from csQport is a curse:
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vagy essek gyógyszsróamóeg eiísgimhaíé skia.or flipping herbal greasy moths.
A találmány egy még alSayösabb nrngvalésítási ssódja a követkszó esopedbói .kiválasztott yegyölwe- vsSSikóZik:An even more preferred embodiment of the present invention is selected from the following esopedos.
vagy ennek gyögyszerészetiieg eifögadbaié-sója,or its euphambad baie salt,
A tiiláimáíty egy meg előnyösebb titegvatósitási módja s köveiközÖ esöportbö; kiválasztott vegyölefre:A more preferred method of dressing the tiles is a sumptuous rain dust; for your selected notebook:
vagy esnek gyógyszerészeíileg elfogadható sója,or they fall into a pharmaceutically acceptable salt,
A találmány kiterjed az előnyös vegyöletek minden gyógyászatiig elfogadható sójára, hldrá'tjára ős vmosipna bmeikti az eiouyö'' \ee,'üktek ke'ÍOtik'k taoíottat i-nnaban k'se/hetnet.. £' ιριιΑλβ Ibtntak a Uh mám mset kopt sk ? v ttonxuk ma *u\ oo', o<'ii,.i« s><! bika jász 'okoban ti együtt.The present invention encompasses all pharmaceutically acceptable salts of the preferred compounds, the parent compound of the present invention, which have been modified to form i-nnaban k'se / hetnet .. £ 'ιριιΑλβ to look after? v ttonxuk ma * u \ oo ', o <' ii, .i «s> <! bull jas' okoban you together.
A találmány szerint? vegyöleteket szabad sav vagy bázis formájában, vagy különféle szervetlen és szerves sasukkai es hnusokkai alkotott sok tonnásában t ülomihettük et. V d\ ott >.0\ a tdet? tilalmam. kotvK' tartoznak \ oen-tosskhí, es t?z?oio«?usa>' kempanbdu \ok kittet.,m haL'Oesak, óvna más, ke.tsbe kamatos ?.ok esetleg űz elkülönítési és tisztítás? eljárásokban használhatók felAccording to the invention? compounds in the form of free acid or base, or in many tons of various inorganic and organic succulents and humus. V d \ there> .0 \ a tdet? ban. kotvK 'belong to \ oen-tosskhi, and fire-oo «usa>' kempanbdu \ ok kittit., m haL'Oesak, would you care about other ke.tsbe interest? can be used in procedures
A fentebb: lesrí: sók előállítására száseos, s szakember áltat Ismeri: eljárás alkalmas. Valamelyik féltő líápleiö vegyület szabad sav vagy szabad bázis törtéé! át például egy-vagy több mélekvivalens kívánt savval vagy bázissal oiyai oldószerben vagy oldöszerelegyben reagáltatha|jnk, amelyben s só nem öldddik. vagy olyan oidőszerbert, például. vízben, .ahöl a. resgáitetás után az oldószert lepárÍáeÍ;sl vagy fagyasztva szárítássá! eltávolítjuk'.Above, the salt is prepared by the skilled artisan and is well known in the art. A jealous topical compound has a free acid or free base! for example, one or more equivalents of the desired acid or base in a solvent or mixture of solvents in which the salt does not die. or a time waster such as. in water, from where. After shaking, the solvent is evaporated off or freeze-dried. removed '.
Más esetben a műnél·; szabad sav vagy bázis ibnnáját egy ioncsetéió gyantás·! engedjük keresztül a sémiéi: kívánt sójának vagy olyan só-formájának előállítására; asaelyet a szokásos általános eljárásokkal egy másik sóvá alakit·· hatónk.Otherwise, ·; free acid or base ibnna with an ion exchange resin ·! passing through to produce the desired salt of Scheme: or a salt form thereof; converts asaely into another salt using standard general procedures.
Amint az: előzőekben emhtehük, a jelen találmány szerinti vegyületek terápiás szerkénttetniősőkben. olyan betegségé liapoiok ereiében, amelyekre koaguláció* rendellenességek jellemzők, igy például instabil angina, nehezen gyógyítható angina, ’nkskartbálü· infarktus, átmeneti iszkémiás roham. ícotnbőzisos szírók, canbóliás sztrók, szétszórt iníravaszktdáris köstgítládiő, ezen belül szepszims sokk ás .mólyvánás trombózis kezelésére vagy n eved \ onáns e í*\ha nv\ ,} « , \ uv s.?< ímmáh » vko« maanöjiah >. >mlns xiavsns \ap\ teszíönőzisánáiea kezelésében aikabspizbaíök. Ezek a vegyítelek alkabaasak Ípvábpá olyan betegségek kezelésé·' re vagy megelőzésére, amelyekben s Xa fókior/paslrotubináz komplex termelődésének és/vagy hatásának szerepe van. Ezek közé számos elvan trombözisos és protrombozisos állapot tartozik, amelyben a. koagoláetös kaszkád aktivált, ilyen többék között, de pesp kizáiölag, a mélyvénás trombózis;, a tüdőemböha, a szivlnlárkms, a í n d, m \,>veo u v> bOvtho'„ ·, o, ; lovoé om,As discussed above, the compounds of the present invention are in therapeutic salts. patients with diseases such as unstable angina, difficult-to-treat angina, necrotic cardiac infarction, transient ischemic attack. scotchbusters, canboli strokes, scattered inira-vascular dressing, including sepsis shock and stinging to treat thrombosis, or n eed by e n * \ ha nv \, } «, \ uv s. > mlns xiavsns \ ap \ test aliases for treatment. These compounds are sub-bases for the treatment or prevention of diseases in which the production and / or action of s Xa foil / paslrotubinase complex is involved. These include a number of relatively thrombotic and prothrombotic conditions in which a. coagolate cascade activated, including but not limited to, deep vein thrombosis ;, pulmonary embolism, cerebral palsy, nd, m,> veo u v> bOvtho '', o ,; lovoé om,
A fentieknek megfelelően. egy nemktvánt úotnbózissai jellemeit állapot emlősben való megelőzésére vagy kezelésére alkaltsas eljárás sorén az e-nlösaek egy talábnány szerinti vegyület hatékony mennyiségét adagóljuk. A lentebb említett hetegseg-állapofökon thimenőén más kezelhető vagy megelőzhető állapot többek körött, de nont kizárólag, az oirarOtiásos o'rtkosroruor Ponmm képződés, antcls tronibobük'a. utapu ragy perkniáa irarísztoraioáiis szlvksísz<íröéj-plaszti.ka következménye lehet, irombosképzödés a vénás érrendszerben, szétszórt inttavaszkalérís koagnlopátia, olyan állapot, amelyben gyors koagniáciös fakioMogyás és szisztémás koaguláció játszódik le, amelynek eredményeként életveszélyes írosobuskőpződés következik be a mikroetezetimn, tani széleskörű azem-sdégtcdcnséghoz, vérzéses szírókhoz, vesedializishez, vérosigénezésltez és szsvkv.tetereze'.he,· vezetAs mentioned above. an effective amount of a compound of the invention is administered to a mammal for use in a method of preventing or treating a condition in an untreated mammal. Other conditions that may be treated or prevented in thymic conditions of the rime states mentioned below include, but are not limited to, the formation of an ortho-orthosroronor ponmm, an antcls tronibobuk. pathogenesis hernia percutaneous iris-toroidal slippery syndrome can be the consequence of iris formation in the venous vasculature, scattered invasive spring-like coagnlopathy, a condition in which rapid coagnative phagocomiasis, and systemic coagulation , leading to hemorrhoids, renal dialysis, blood-germinating and ssvkv.tetereze'.he, ·
A találmány szerinti vegyületek biológiai mintákban a koaguláció gátlására alkalmas eljárásban is használhatók, -amelynek során egy találmány szerinti vegyületet adagolnak,The compounds of the present invention may also be used in a method of inhibiting coagulation in biological samples by administering a compound of the invention,
A laiáímány szerinti vegyületek más terápiás vagy diagnosztikai szerekké! kómbmáéíöban is alkalmazbatok. Bizonyos előnyős megvalósítási módokban a találmány szerimi vegyüieteket más, ilyen állapotok esetében az általánosan, elfogadotí orvosi gyakorlmml összhangban jellemzően felírt vegyüiéíékkéi, például koísgoláoséelienes szerekkel, tromhoiitlkas szerekkel wgy más .nuíkfumbotiMmookknl,. ezen Eeiai vériemé eke-aggregáeió gátlókkal, szövet plazminogén aktivátorokkal, tünk mázzal, protsrokmázzsl, sztreplöldoázzsl, beparinnai, aszplrinpei vagy svarfarinoai együtt is adagöíbatjnk. A taisimápy szermil vegyületek szieetgetikusan hathatnak egy sikeres tromhoiitlkas terápiái köveiben az ájraelzáfődás megelőzésében és/vagy a reperfáziő idejének csökkentésében. Ezek a vegyületek lehetővé tehetik az alkalmazandó tromboiiííkrss szerek dőzisátiak csökkentését és Így minimalizálhatják a potenciális vérzéses .mellékhatásokat, A jelen találmány szerinti vegyüle\ k ' >>'t i'i's !ft,'ik >kh<n , i\m vs, d\, piáimon \b,n ·>! i ö'< nf' Ui'sí'h ' sertésekben, kutyákba?!, patkányokban és egerekben, vagy m vip-o használhatók,The compounds of the present invention are other therapeutic or diagnostic agents! I also use it in cobwebs. In certain preferred embodiments, the present invention provides serum compounds with other compounds typically prescribed for such conditions in accordance with generally accepted medical practice, such as anti-coagulant agents, thrombolytic agents, and the like. this Eyelid is also coadministered with inhibitors of plum aggregation, tissue plasminogen activators, glaze, procrochase, streplolase, beparin, asplrinp or svarfarin. Synthetic sermyl compounds may act as a sedative agent in the stones of a successful thrombolytic therapy in preventing and / or reducing reperfusion time. These compounds may enable the use of thrombolytic agents to reduce the dosage and thus minimize potential bleeding side effects. The compounds of the present invention may be used to reduce the amount of bleeding side effects. d \, in my pajamas \ b, n ·>! i ö '<nf' Ui'sí'h 'in pigs, dogs?!, rats and mice, or m vip-o,
A jelen találmány szerinti vegyületek biológiai tulajdonságait a szakterületen jól ismert módszerekkel, példán! az is visz? proteáz- akti vitás meghatározásával és a trombőziseüenes hatékonyság és a hemosztázisro és hematológiai paraméterekre gyakorolt hatások 1« v/vf> vizsgálatokban való értékelésével állapíthat jak meg, amint azta példákban betnntmjnk.The biological properties of the compounds of the present invention are well known in the art, e.g. does it take you? determination of protease activity and evaluation of anti-thrombotic efficacy and effects on hemostasis and haematological parameters in 1 v / vf assays as described in the examples.
' ' 3 te < >3\ 'ff >t < , \ \ ' i '- 'í >,t , i,i d s< \ s , <Ί \{ vtelte tte \te »\> ' \ χ > ‘5 b-mo adagolható tabletták, tetttendak \ gp eifoftes. Kúpok, sajelmnás utj,tu outemi dkiilm;gtei.íru Pte’d oldatok vagy szuszpenzlók formájában vagy formált tárgyakba foglalva adagoibaíjok. A találmiiny szerinti ysgybtéíókól alkalmazó kezelést igénylő «gyedeknek (jellemzően emlősöknek í olyan dózisokat adhatunk be, amelyek optimál lis hatákonyáágot'biztosítanak. Az ifosgoíés ifozlsa fe módja egyediről ügyedre, és többek közölt a· kezelt emlős flpíisátó!, araiak nemétől, tusttömagátől, táplálkozásától, párhuzamosait folytalötí gydgyszórézéaóföl. általános klinikái áilapotátó.!, az: alkalmasat vevőietektől, a .Speciális alkalmazási»!, ahiéíyhS ezekéi a vegyületeket basa·· váljak, és más tényezőktől'foggőeo véhoKÍk, amelyeket a gyógyítás terü letért jártas szakemberük ismernek.'' 3 te <> 3 \ 'ff> t <, \ \' i '-'í>, t, i, id s <\ s, <Ί \ {vtelte tte \ te »\>'\χ>' 5 b-mo dispensable tablets, pretenders \ gp eifoftes. Suppositories, syringes, diluents, in the form of Pte'd solutions or suspensions or in molded articles. Predators (typically mammals) requiring treatment with the present invention for therapeutic use may be dosed to provide optimal efficacy. Parallel therapies are generally available from general practitioners, such as: are suitable for use by customers, and are intended for special applications, such as, and other factors known to those skilled in the art of medicine.
\ v v rh’w ve<n teg\ < a, k ι i r > n\ .o kés n'ntertete ii < k< \ im uí,ví s ípbot ,i tg! iá·· oh ! todvn. hvgs a kívánt tisztáéi toka sepateset 'ííiofogiaAjo etfog,«Iható hordozol, kai, eseigseesikkel, sbfodízáforökkal ás basöö.ló anyagokkal kevepák, ős ezt követően nyögött vagy Időzített kátóaryag-leadásö készítményekké alak írjak. A terápiás alkalmazásra elfogadhsítő hordozók és higító&oyagok a gyógyszerészet területén ismerték, és például a Remington’s kbartnaeetttteai' Se tettess (Maek Fnblishing Co,, A. M>. Ctermase szerk,, 1.983) című kézikönyvben le vannak írva, Az ilyen· anyagok a merpsensm nézve nem mzlkasak az: aík&i·' i ' ·. v sok i >·. aiitom,» η <, i ‘1 i ki t \ kteófo < n '♦ suti .Ί naás szerves sav sókat tamthnáz» püftbrókóf, amfoxídánsekat! Így rtezköfomsavaí, kis oiolekofatömegű (tömé! kevesebb maradékból áHő) pepödeket, például pöharglnint protemakek például széfismálbáUllég zsőlaiint, vagy iau»onglobnlim>kák hidrofil polimeteket, így pnlgvlnilpfo-nlidötte!, amioosavakat, példán! gífolak gluraminsavsb aszparaginsavavagy argtninl, monoszaehandokat, diszaeharídokat és más szénhidrátokat, ezren bakii eelintózr vagy származékait '* s, a '(Vt ug \ t' \ ut k< < s *· i ki t fcs i t 1 ' if u kimuknaarokas, rav rnannkm ·' >\ v t'< o e . .IKK,. - 1' υ i< a , \ >.p ' 'tton >χ I ' itetev , \< ,osat. sgv rsveemt, -P járomé* -öt vagy p»l istliéng! Ikölt foglalItalnak snagokbam\ v v rh'w ve <n teg \ <a, k ι i r> n \ .o knife n'ntertete ii <k <\ im uí, ví s ípbot, i tg! i · · · oh! todvn. hvgs the desired purity of the sepateset lophiophage Ajo, which is intended to be formulated as a drenchable carrier, a dropper, a first-aid, a bleaching agent, and a basal substance, followed by a groan or a sustained release. Acceptable carriers and diluents for therapeutic use are known in the pharmaceutical art and are described, for example, in Remington's kbartnaetetttei 'Se tegess (Maek Fnblishing Co., A.M., Ctermase Ed., 1983). not mzlkasas are: aík & i · 'i' ·. v sok i> ·. aiitom, »η <, i '1 i ki t \ kteófo <n' ♦ suti .Ί nasal organic acid salts tamthnáz» pyrite, amphoxidants! Thus, low-molecular-weight (less than residual) pellets, such as phtharglinin, protemacs, for example, contain saline, or more hydrophilic polymers, such as pnlgvlnylphthalenylphenol, glypholac gluramic acid aspartic acid or arginine, monosaccharides, disaccharides and other carbohydrates, thousands of bacilli precursors or derivatives '* s, a' (Vt ug \ t '\ ut k <<s * · i ki t fcs it 1' if u kimuknaarokas, · '> \ V t' <oe .IKK,. - 1 'υ i <a, \> .p' 'tton> χ I' itetev, \ <, parts. Sgv rsveemt, -P yard * or p »l istliéng! Spend itIt contains snagokbam
A terápiásán alkalmazásra szánt találmány szsrirm. dógiskészrnrtenyöknnk sterileknek kel! lenniük. Autó* rlfozési könnysn megvaléskítatjök steril membránon,, például Ö ,2 mikronos' membránon át végzett szütássei, vagy más hagyományos: módszerekkel. A készrUnényekeí jellemzően lioplizáll tormában vágy vizes oldatként tároljuk. A találmány szerinti készítmények pH-ja jellemzően 3 és 11, előnyösebben 3 és 9, ás legelőnyösebben 7 és k közötti. Bizonyos lenti excipiansefc». hordozók vagy stabiiizáíerok: alkalmazásakor iehnészéiéséa gybrös poiipeptidsők képződnek. Noha az adagolás előnyös módja az injektálás, más adagolási módszereket, példáid érába, rnimseií,ri (betesz és ^ag\ sntezíO fonna abant, s.'uhfoü.tn, ínüanu»,.'fojiáris. sasfagbifoe tettetek téktahv nazális, iranszdermáite vagy iníraperiíooeáüs adagolást is alkalmazhatnak, amelyekhez: különféle dózísfonnáknt, így köpokat, implarttált peilefeket vagy kis (ampereket, aeroszolokéi, orális dóziskészlimónyeket és toplkáljs készkuiéiiygkeb így kenőcsöket, cseppeket és éerísiáife t3p3.szo.kai használhatunk, A találmány szerint,! vegyülő* teket előnyösen formáit tárgyakba, például smplantátomokba foglalják» .amelyekhez közömbös' anyagokat, Így teoteua.,<te .etemteate ph.tehk<! usiö ntrtd.«' -c 'kosm-m pri.kisd teltette et, s«' di'tepun t M>'\ n\t‘, a kereskedelemben kapható polimereket kaszuáteok.The invention is for use in therapy. we need sterile medicine! be. Car refinement is easily accomplished by sterile membrane blasting, such as through a? 2 micron membrane, or by other conventional methods. The finished product is typically stored in a lyophilized horseradish craving aqueous solution. The pH of the compositions of the invention is typically between 3 and 11, more preferably between 3 and 9, and most preferably between 7 and k. Some lent excipiansefc ». carriers or stabilizers: when used, they form lumpy polypeptide salts. While the preferred route of administration is by injection, other routes of administration, for example, include the administration of nimesal, intravenous, or transdermal administrations of the oesophageal sphincter. Dosages may also be used for which: various dosage forms such as sputum, implanted eyelets or small (amps, aerosol, oral dosage form and topical formulations) may be used in the form of ointments, drops and emulsions. , for example, in my implants, ".to which inert substances", So teoteua., <te .etemteate ph.tehk <! usiö ntrtd. «'-c' cosm-m pri.kisd passed et, s« 'di'tepun t M> '\ n \ t', commercially available polymers are cascaded.
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Λ. toláiináíty szeripll vegyidefekei: ásditestélö antitest imiődentutnok, növekedési táktorok, hoímeook vagy tnés eétbajntfetó sw^wslek alkalmazásával Is adagolhatják, amelyekhez a vegyidet molekulái! hoaKákapesob juh, Λ találmány szerint? vegyüleíeket szer-eólbajnttató hordozöként megfelelő polimerekkel ts kapcsolhatjuk. Ilyenpolimerek'többekközött a poHévInlipirroíidinon), plráü-kopnOWA poiifhidt«xipíyipiirimétakrikanid.::fettöt:, poikhidroxie·ily-aszp&rtamiő-fénoi vagy a puli·edténostdbpoiiiizir, amely paltustoil-tnaradékokkal helyettesített, Ezen túlmenően a találmány szerinti vegy&leteket biológiáikig lebontható polimerekhez is kapcsolhattak, amelyek a hntősnyag szabályozod leadását teszik' íeketövá, ilyen, példáéi a polHejsasv a polígOkelsnv, a m os p<<hghk’sss k»>peh»iO!at a puhup'-'ik'.»kat'tokAt,>nk a pulit hxltm»n»ys a, y a polnoOui»len»® a pohacetálok, a jxdi(dihidropiránok). a poliCciaftoakriláltsk.} és hidrogéiek térhálós vagy amfipalüiits blokkxopvif'í » \ p<»h \»e\'o »te est, >s,tepo' »i m - v\ári \amd p\ ' ^rtiO^t »x ”to két, csöbevezétést, protéziseket és hasonlókat: készlthétöpk,Λ. Tolerated Seriphylaxis: Using a bodily antibody such as an infant, a growth factor, a homeook, or the like, it can also be added to which the molecule is a molecule! hoaKakashob sheep, according to the invention? the compounds may be coupled with suitable polymers as a vehicle excipient. Ilyenpolimerek'többekközött the poHévInlipirroíidinon) plráü-kopnOWA poiifhidt «xipíyipiirimétakrikanid :: Fett., Poikhidroxie · so-aspartic & rtamiő phenol or pull · edténostdbpoiiiizir substituted paltustoil-tnaradékokkal, addition Dry & port to new platforms of the present invention to associate degradable biológiáikig polymers which make your controlled release of the substance "black," such as polHejsasv is polygOkelsnv, where p <<hghk'sss k »> soft» iO! at puup '-' ik '. »kat'tokAt,> nk is pulit hxltm »n» ys a, ya polnoOul »len ® ® the polycetals, jxdi (dihydropyrans). the polyCciaftoacrylate} and the hydrogels are crosslinked or amphiphilic block xopvif »» p, »t, tepo» »im - v \ ari \ amd p \ '^ rtiO ^ t» x ”To two ducting, prostheses and the like:
A hatásos vegyületet tariahpazó folyékony késrittnéayeket általában hatályba, amelynek steril iiozzáföré» si nyílása van, például intravénás oklatós zsákba vagy fiolába helyezzük, amelynek injékciös tűvel átszűrható dugója van,The active compound is generally effective in a liquid lozenge with a sterile lozenge opening, for example, in an intravenous training bag or vial having a stopper that can be filtered with a needle for injection,
A tempósan hatekons ,1,ί.ο\οΚ,ό ot w osoet ot >,».'»medi</ei ékkel hatat rohadok tnea Minden egyez találmány szerinti vegyület esetében egyedi meghatározásokat végezhetünk a szükséges optimális dózis inegáilapltására, A terápiásán hatékony dózlsíartományi azadagolás módja, a terápia -célja és & beteg Állapota befolyásolja. Infekciót; tövei való stöektálás esetéin a dózist a testfolyadékokba adjak. .Más adagolási módok esetében a felszívódás hatékonyságát egyedileg kell isegbgíározói nshtóáp vegydlette á finmákblógiáháh jói: femért thőőszérakv k< i t stna\ nxgte >d-,x * -zékscgw kbat, hoc·, a kr/e'o e>\»« a (.koto r>eaíik»4 os az adavri.v, modka n.odost'stt a szükségnek megfelelőéit ahhoz, hogy optimális terápiás hatást kapjon. A hatékony dózlsszioteknek, azaz azoknak a dózlsszlntóknek a maghatározása, amely a kívánt ereöméhy eléréséhez sztlkséges, a szakember feladata, A vegyniéfeitói: jóifemrifen alacsonyabb dőzlsszinteh kezdtük adagolni, és a dózisszíntekot addig hövelikk, amíg a. kívánt hníáví él gém érjük,With the help of the fast-acting, 1-oz.ο \ οΚ, ό ot w osoet ot, medication, each of the compounds of the present invention can be individually determined to provide the optimal optimum dose required, the therapeutically effective dose range. dosing regimen, therapy goal and & patient status. infection; in the case of stinging the stems, the dose should be administered in body fluids. For other dosage regimens, the effectiveness of absorption should be individually adjusted by the dietary agent and the dietary gland: germinated corpus luteum dc, x * -greencat, hoc ·, kr / e'o e> (.koto r> eaikik »4 adavri.v, modka n.odost'stt is necessary to obtain the optimal therapeutic effect. Determining the effective dosage regimens, i.e. the dosage regimens necessary to achieve the desired power output, is It is the task of the expert, from the Chemical: we started to add a good femrifen to a lower level of steam and increase the dosage color until the desired hníáví live boom is reached,
A lalálmány szerinti vegyüietekel orálisan vagy pamnterálisan körülbelül 0,1 és 100 tngkg, előnyösen .körülbelül ö,ö és űö mglkg, és előnyösebben körülbelül l ás 20 mgdtg hatékony menaylségben napi egyetlen vagy 2-4 oszlott dózis, és/vagy íbíysntalos iníöziö formájában adagoljuk,The compounds of the invention are administered orally or parenterally in an effective dosage of about 0.1 to 100 mg / kg, preferably about 0.5 mg / kg, and more preferably about 1 to 20 mg / kg, and / or in the form of single or 2-4 divided doses per day, and / or. .
A körülbelül 5-SÖO mg találmány szerinti vegyületet vagy vegytdetkeveréket jellemzően szabad sav vagy bázis forsnájábah vagy győgyászatílag elfogadható- sóként fiziológiásán elfogadható vlvőanyággak hordöxővtd, exclpfeossei, kötőanyaggal, tartósítószerrel, .stsbilizátorrai, színezékkel és ízanyaggal iörmaíáljuk az·:elfogadott gyógyszerészett gyakot latnak megfelelően. A hatóanyag mennyisége ezekben a készítményekben olyan, hogy alkalmas dózist- kapónk a fentebb említett?dáafeiaí'tómáayfeaa.Typically, about 5 to 50 mg of a compound or chemical mixture of the present invention is formulated with a free acid or base, or a physiologically acceptable pharmaceutically acceptable carrier, excipient, binder, preservative, colorant, stabilizer. The amount of the active ingredient in these formulations is such that a suitable dosage recipient will be the one mentioned above.
Az adjnvánsok; aófeiyahet a bfefeitákba, kapszniákba vagy hasonlókba foglalhatunk, jelieinzöen kötőanyagok, példáid akstanézga, kukoricakensértyíid vagy zselatin, ét: excipiensek, példáéi orikrokrlsfelyos cellulóz, szétesés!: elősegítő .szerek, így knkoribakeménykő vagy slgínsas, kenőanyagok, így magnéztum-sztearát, édesítőszerek, például szacharóz vagy iaklóz, vagy Í zes kőanyagok. A kapszula dózlsíbrnta a fenti anyagok mellett folyékony hordozóba!, Így vizet, söoldato! vagy zsíros olaja! is tartalmazhat. Különféle más típusit anyagok is használhatók például bevonatként vagy a dózisegység fizikai formájának módositásám. Injektálható ttíertl készítményeket a hagyományos gyOgysxcsSszetí gvakoöatnak megfelelően ádtthatnnk elő. A hsiásös vegyítlefeek például.égy vivnunyághiiü, például égy öiajbáh vagy szlüiáökué zsíros vivÁaöyágbáti, például etlboleáibati váló oldása vagy sznszpendálása vagy iíposzótnáha iógl&lása lehet kívánatos. Az ©fogadott gyógyszerészen gyakorlatnak megfelelően a készítmények poiterekel, íartósliószerekvi, amloxidáíisoka; és hasonló anyagokat Áriáimazbatnsk,The adjectives; The auxiliaries may be included in the formulations, capsules or the like, preferably excipients, e.g. or lactose or Flavored stone. The capsule was dosed in a liquid carrier along with the above materials, so water, brine! or greasy oil! can also be included. Various other types of materials can be used, for example, as coatings or to modify the physical form of the dosage unit. Injectable formulations may be administered in accordance with conventional methods of administration. For example, it may be desirable to dissolve or suspend a fatty vivacea, such as ethyl oleaginous ointment, or liposomal fatty ointment, for example, in the form of a fatty oat or a fatty oat or an oily flesh. According to accepted pharmacist practice, the formulations are poiterelic, oily, amloxidic; and related materials in Ariaimazbatnsk,
A vegyületek előállításaPreparation of compounds
Λ jelen találmány szerinti vegyületeket szilárd vagy folyadék fá/isn ehumsokkak umefoeket skmdntd szukköny vekben írnak le vagy amelyekre ibeu könyvekben hivatkoznak. vagy a két módszer kombinációjává! állma κ v f t é\ t i'tnis-o.'k okién et n jó onei Λ >sd ..cg,© Bmv- fo In jfo< rk of Pepiidé Syr-lhesis ÍHsfneret al.. Szetk., Springer-Vetíag. Berlin, 1984) ehrái könyvéi.Vegyületek The compounds of the present invention are described in solid or liquid wood shocks, or referred to in ibeu books. or a combination of the two! state κ v f t é \ t i'tnis-o.'k okién et n good onei Λ> sd ..cg, © Bmv- fo In jfo <rk of Pepiidé Syr-lhesis ÍHsfneret al .. Setk., Springer-Vetíag. Berlin, 1984).
Az: említeti módszerek bármelyikében alkálmázött kiindulási anyagok & kejeskeóeleinboa, például az Aldfíeh, Slgipm Nova Bíoehemicals, Baehem Bioseietices és hasonló cégekről beszerezheiOk vagy isméit eljárásokkal könnyen elöáillíhaíők,The starting materials " alkali-alkalized " or any of the methods mentioned hereinabove are readily available from Aldehyde, Slgipm Nova Bioehemicals, Baehem Bioseietices or similar processes,
A reakciókat standard lateatóriaml uvegeszközbkbefi és róskelóedényekbeti végezzék standard hóméisékieií- és nyomás-körülmények közön, kivéve ha arra másképpen utalunk, kzeo vegyüfoiíik szíuidzíse álad az ezekben az eljárások t?ao aikaboazeü amlnósav-származékok inokclós esoporljaít blokkolöesopertokks! védjük a kapcsolási eljárás alatti kei-eszt-reakelók átegeidzésére, Az alkidinas blokkoló csoportokra példákat és azok alkelmnzását a The Peptsdes: Anslysis, Syothesis, Btólögy” elhitt könyv (Aeadernie Press, Oross ei al., Szerkó 3, (lósliés 9. j 1987) kötetében írják ie, amelyek iartabna múlás iórmó.iá·· bán a jelen leírás részét képezi.Reactions should be performed in standard lathe devices and flasks under standard conditions of snow and pressure, unless otherwise noted, the fiber in the chemo-solids is blocked by the inhibition of the amino acids blocked by these processes. protects the overlapping of keyless reactants during the coupling procedure, Examples of Aldidine Blocking Groups and Their Subdivision in the Beloved Book of The Peptsdes: Anslysis, Syothesis, Boltögy (Aeadernie Press, Oross et al. ), which are part of this description.
A találmány szerkői vegy-üleseket a szakterületen jól ismert eljárások alkalmazásával sziatoilzálhaijok. A reakAóteriuékeket eikülöoktük és hagyományos rendszerekkel jeifon-zöe:· egy kompatibilis oldószerbe töftónö oldószeres extrakciövai tfeztítjok. A termékeket nsziopkitnaatográitás vagy más alkalmas módszerrel tovább tisziiihaijnk.The present invention provides structural chemicals using siatoylsalicyls using methods well known in the art. Reaction solutions were bypassed and conventional systems were characterized by: · completion of solvent extraction belts into a compatible solvent. The products are further distilled by ophthalmic tomography or other suitable methods.
Készítmények és formulákPreparations and formulas
A. találmány szerinti vegyületeket szabad sav vagy bázis tormában vagy külöuléle szervetlen vagy szerves savakkal és bázisokkal alkotóit sók formáidban knlösithetjük el. Az ilyen sók a találmány körébe tartoznak. A ncm-tövkus e;. íízmfog usm konmanb.h, sok kiUnoósim hasznosuk, nohu a i-etvabe Sutusnaoo sok o alkuim,tzasra keiél 1íszínek az eikülónácsi és tisztítási eljárásokban,A. The compounds of the invention may be isolated in free acid or base horseradish or in the form of salts with various inorganic or organic acids and bases. Such salts are within the scope of the invention. A ncm-labor e ;. taste tooth usm konmanb.h, many of my students are useful, nohu a i-etvabe Sutusnaoo many of my talks, tzasra change colors in eiculture and cleaning procedures,
Számos ötödszer használható a lentebb leírt sók ftlöállitásáeá, amelyeket a szakemberek isnssrnek, így például egy fentebb eotüíeb szerkezeté vegyidet szabad sav vagy bázis formáját egy vagy több roólekvivaíens kívánt savval vagy bázissal oldószerben vagy öidószsreiegyben, amelyben a só nem oldódik, vagy olyan oldószerben, például vízben reagálón jók. amely oldószerben végzet· reakció után az oldószert lepárlással vagy fagyasztva szárítással eltávolítjuk. Más cselben s termék szabad sav vagy bázis formáját egy ioncserélő gyantán engedjük kereszd.ll a termék kivárd {-ójának vagy olyan sö-fonnájának előállítására, amelyet a szokásos általános <. i Jso'-k, i < '< !' Olk Sv ' ! > O !Many fifths may be used to prepare salts described below that are known to those skilled in the art, such as the free acid or base form of a compound of the above type with one or more roe equivalents of the desired acid or base in a solvent or solubility such as they are reactive. after completion of the reaction in a solvent, the solvent is removed by evaporation or freeze-drying. In other embodiments, the free acid or base form of the product is allowed to be searched on an ion exchange resin for the preparation of the expected product or salt of the product, which is customary for general <. i Jso'-k, i <'<!' Olk Sv '! > O!
A terápiásán hatékony dózisokgt A νύζ-ο vagy A vívó inödszerekkel határozhatjuk, üteg;. Mindóó egyes találmány szerinti vegyület esefében egyedi meghatározásokat végezhetőnk a, szükséges optimális dózis mog.áüapiló tusára. Λ terápiásán hatékony dózistartományt természetesen az adagolás módja, a terápia eélja és a beteg állapota :befolyásolja-. tsjekeió-s tűvel veié InjekWás-esetén a dózist a. testfolyadókökba adjak. Mas adagolási módok esetében a tetszfvödas hatékonyságát egyedileg keit meghatározni mtntíen Inhibitorra a farmakológiában jói s i I il‘ lí,! \fo 1 !U ,t U. t il 1 ! \<0k X Ili Λ Ά ! fo \ ó O < <' te \ is; i< 1>< < 1 módját módosítsa a szükségnek megfelelően ahhoz, hegy optimális terápiás hatást kapjon. A hatékony dózísszíutetetek, azaz azoknak a dőzisszánteknek n meghatározása, amelyek & kívánt eredmény eléréséhez szükségesek, a szakember-foladala, A vevőieteket 'jellemzően -alacsonyabb dázisszintenkezdjük adagolni, és a dőzfemleket. addig aöveljük, amíg a kívánt hatást et nem étjük.The therapeutically effective dose regimen may be determined using the νύζ-ο or A fencing devices; For each compound of the invention, individual determinations of the optimal dose of the drug to be administered may be made. Λ therapeutically effective dosage regimen, of course, the route of administration, and patient therapy eélja the condition: befolyásolja-. using a needle for injection, the dose was injected with Injection. I give it to my body drains. For mas dosing regimens, the efficacy of any drug should be individually determined for Inhibitor pharmacologically well. \ fo 1! u, t U. t il 1! \ <0k X Ili Λ Ά! fo \ ó O <<'you \ is; Modify i <1><<1 as needed to obtain an optimal therapeutic effect. Determination of effective dose flaps, i.e., the nozzle slots required to achieve the desired result, is accomplished by those skilled in the art, typically starting with a lower gas level, and vapor flakes. increment until the desired effect is eaten.
.A találmány szerinti vegyületek jellemze dózisa körittbelöl 0,001 ntg/kg és körülbelül 1000 mg/kg, előüybsen ikörűlbélhl 0,01. mg/kg és körűtbelüi TOO mg/fég, és előnyösebben körülbelül 0,1 mg/kg és 20 tttg/kg kőzöiti. Előnyősén a taiüitnány szerinti vegyületeket naponta több dóözisban adhatjuk he. de más adagolás Is hasznos tehet.Typical doses of the compounds of the invention are from 0.001 ntg / kg to about 1000 mg / kg, preferably from 0.01 g / kg. mg / kg and around TOO mg / kg, and more preferably between about 0.1 mg / kg and 20 tg / kg. Preferably, the compounds of the present invention may be administered in multiple doses daily. but other dosages can also be helpful.
A találmány szerinti eljárások gyakorlati meg valósítása során s találmány -szerinti vegyületeket önmagoke t ·. -g, te m η , i $ j u n ,t\ , ; p ,ι-, >\ ,’t e χ í\ , υ et ki u pn i > ron ki ok B>/o n es előnyös mmatessüte mődokfom a idea tsiat nunY wnnti veuyük-teket ma?, dmn állapotok eseteken ,-.z általánosan elfogadott orvosi gyakortaitat összhangban jellemzően felírt v^'ölefekkol, -például .koagulációelleoesszerekkel, trohtbólitikus szerekkel vagy más ^ttirtombotikumokkaf, ezen beiül vétiemezke-aggregáeió gátlókkal, szövet plazminogén aktivá-urokkal, urokíttázzai, protnokinázzal, $zteeptetkfoázz.ah heparinnal, aszpirinnel vagy waríárínnsi együtt is adagolhatjuk, A íniáiniány szerinti vegyületeket ói vívu rendszerűt emlősökben, igy főemtosiAber, például cnfoetekhen. birkákban, íosuktno tehenekben, sebesekben, LorsákKm, ptkansokban és égőitekben, vagy -íh-vlrm használhatjuk.In the practice of the methods of the invention, the compounds of the invention are self-seeded. -g, te m η, i $ j u n, t \ ,; p, ι-,> \, 'te χ í \, υ et out u pn i> ron out ok B> / on es advantageous mmatessüte mődokfom the idea tsiat nunY wnnti veuyük-ma today ?, dmn states, -. z generally accepted medical practice in accordance with typically prescribed anti-inflammatory drugs, such as coagulation anti-inflammatory drugs, trocholytic agents or other anti-trypticotics, including antiplatelet aggregation inhibitors, tissue plasminogen activators, urokineticase, It is also contemplated that the compounds of this invention will be administered in mammals of the prime mammalian species, such as cephalosporins. sheep, losuccno cows, wounds, lorsk, m, ptkans and burners, or -ih-vlrm.
A jéien találmány szerinti előnyős vegyi-letekre jellemző, hogy gátolják a trombtnképzödésl, mirneiielt elfogadható hatást gyakorolnak a köagniáéiós paraméterek klasszikus értékéire.. a vérieníezkékre és vérierüezke'működésre, valamint elfogadható szintűek az alkalmazásukkal társuló vérzés! komplikációk. A nemkívánt trombózissal jellemeze» állapotok többek között őz artériás és vénás érrendszeri érintő Ilyen állapotok.The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation, have a mildly acceptable effect on classical values of coagulation parameters, and on an acceptable level of bleeding associated with their use. complications. Conditions characterized by unwanted thrombosis include deer arterial and venous vascular disorders Such conditions.
A szIvkaszonVverÖénendszert iliefoéa: .abnormális trombnsképzödés- jellemzi a Kialakult ateroz\k ív sí s f 1 m eteiMil sí m 't( ss<in! t,s,l< i »e ι < s o\t uurwi z/íi Vi'tev usMisouiei e ionAep,ei\s mm w χ a tmn vho\ λ ut n i\uy u pu\( fo t. <m\ itnn di·- , ekos/nu ár-plasztika (perettíaneous nanslumina! eoronary angioplasty, PTC.A) következménye.The cardiovascular system is characterized by : abnormal thrombus formation - characterized by the formation of atherosclerotic curve 1 m etiMil ski m '(ss <in ! T, s, l <i »e ι <so \ t urine). usMisouiei e ionAep, ei \ s mm w χ a tmn vho \ λ ut ni \ uy u pu \ { fo t. <m \ itnn di · -, ecos / nu price-plastic {perettíaneous nanslumina! eoronary angioplasty, PTC.A ).
A vénás érrendszert lek intve abnormális trombosképződés jellemzi az alsó végtagokban vagy sz sIható területen végzett nagy műtéteken átment betegekben megfigyelt állapotokat, az -ilyen betegek gyakran szenvednek itz érinted végtaghoz j-rtó véráram esőkkertése következtében a vénás étrps-idszerhen létrejövő tromhttsképzödéstői és a íüööéüibóha pmdiszpözfoiőiáíők Abnozoiáiis ttömlimsképziidés jéllénizí továbbá a szétszórt nn ss js<ku ett 'uiiy\i<i i'i> t u nfo,tt fo-'te u> au e i cs kí,í t-.te < fo 1 \ ' οχ ok, í'/'vmw sós fertőzések és iák sorén, egy olyan állapot, ahol gyors a kosguiáeiős faktor-fogyás és a szisztémás koaguláció. , > ek xev.íte-.s i 1' ib! skep ,<k ,j <; ü.c , <. y ' »\5i\ ·. , ^fbm o -,.1-.1,0 U \Í>U'~Abnormal thrombosis in the venous vasculature is characterized by conditions observed in patients who have undergone major surgeries in the lower limbs or in the inguinal area, such patients often suffer from ureteric thrombosis and thrombosis due to rainfall in the affected limb In addition, the image of the heap also improves the scattered nn ss js <ku ett 'uiiy \ i <i i'i> tu nfo, tt fo-'te u> au ei cs kí, t-.te <fo 1 \' οχ ok, í '/' vmw in saline infections and strains, a condition in which there is rapid coagulation factor loss and systemic coagulation. ,> ek xev.íte-.si 1 'ib! skep, <k, j <; ü.c, <. y '»\ 5i \ ·. , ^ fbm o -,. 1-.1,0 U \ Í> U '~
-eieeieiensegheí vezet-eeeieienseghe leads
A tilalmam szeism. segröleteket, amek-ekei a? irt leüt módón \foas?mnk ki es atkabn-iznnk, .Pknínsasi ,A ta iu>k neuikss t tt ό táv üss,- g i '«tett '1 ei'VX evsJc \ ig\ ken esés, u , p.k 4,1 ta> mn n -etMy ban is seism. shakes that are? write off \ foas? mnk ki es atkabn-iznnk, .Pknínsasi, A ta iu> k neuikss t tt ό distance üss, - gi '«made' 1 ei'VX evsJc \ ig \ ken fall, u, pk 4, 1 ta> mn n -et
1?1?
iromltozis által közvetített akut szívkoszorúér szhtdröota, ezen belül szívinfarktus, instabil angina, nehezen gyógyithatö angina, elzáródáses szívkoszorúér dombos kezelésére vagy megelőzésére, antí írombulíííkns terápiás:for the treatment or prevention of acute coronary artery disease mediated by iromltosis, including myocardial infarction, unstable angina, hardly treatable angina, occlusive coronary artery disease, anti-thrombolytic therapy:
\ >., w V, o upi 1' -\<ίϊ\> O x\ ' k! v' 1 <! IuImO , OUÚ s }s íl\i Y'Oí i itt i\ <hlo ο,ΚΗ* \ szindróma, többek között etnböhds szhok. ttorttbőzisns sztrők vagy úiuteaett tszkénuás róhatnék kezelésére vagy megelőzésére, (c) báonilyén -ttőínbógíSőS' szlodfőmá kózeiésére vagy megelőzésére, entély a vénás rendszerber? to> ti . ek\ Ί\, 1 λ vkkuo.v. kos'S>i\ ,\,íg\ e tddi'-m bob s ,-mel\ w gsm t,m \,,m sowm dekao>,te, műtét vagy sérülés kövslksztéberí alakul ki, (d) bfertliyett koagolopoátia kezelésére vagy megelőzésére, többek között szétszórt tntravaszkulárts koaguláció (amely többek között szepszises sokk vagy snés fertőzés, máiét, terhesség, sérülés vagy josszsadulatúság következményig és vagy társul több szerv elégtélgnségévOí vegy nőin}, iropibózb vo. tíood«O0gvmf,rs purpurn, thrmnbounguue ebbteruas mgy h<,p,mu eltel kiváltott ttombncuopemá\u! társuló u ό tv s utót >-? m'\k's«.ie s , , κ 1 ,>\'s<.a u > t 0 m »'t\ >·, ko ti dska, tok s, réséi inuk i<e re, amelyek testen kívüli keringéssel (például vossdótliztssel, szív-tüdő bypass műtőből vagy -nás mtigénezésl eijárássak plazmaíérézissei) támdtoik, (í) fromhőzisös szövődmények kezelésire \ogy meueióiesi'm, amelyek műszerezéssel (például szív- vagy más túlra vaszkulát is kátéim -'es. mim -tort,a b-d'utu pumpa, kos>oráér-tágiíő vagy ssbvbílieetyű áikabnázásávul}, és (g) amelyek protézisek behelyezésével társulnak.\>., w V, o river 1 '- \ <ίϊ \> O x \' k ! v '1 <! IuImO, OUÚ s } s l \ i Y'Oí i here i \ <hlo ο, ΚΗ * \ syndrome, among others, ethnböhds shok. Could I use it for treatment or prevention of strokes or new teacene, (c) Baronene, for the treatment or prevention of slime, for the venous system? to> ti. ek \ Ί \, 1 λ vkkuo.v. kos'S> i \, \, prom \ e tddi'-m bob s, -mel \ w gsm t, m \ ,, m sowm decao>, you, surgery or injury develop obesity, (d) treat or prevent bfertliyett coagolopoathy , including diffuse tntravascular coagulation (which results, inter alia, in sepsis shock or snail infection, malnutrition, pregnancy, injury, or goiter and is associated with multiple organs of malnutrition in a woman), iropibosis v. tíoodu <m p, mu el evoked ttombncuopemá \ u! associate u ό tv s after> -? m '\ k's «.ie s,, κ 1,>\' s <.au> t 0 m» 't \> ·, ko such as dorsal, cavity, and slit gaps that are invoked by extracorporeal circulation (e. g., vossdot lysis, cardiopulmonary bypass surgery, or plasma mythigenesis), (i) from the treatment of myocardial complications. for example, my heart or other over-vasculature is my cat mim tort, the b-d'utu pump, ram> ora, or ssbvbillie, and (g) associated with the placement of prostheses.
Az aniikoaguíáns terápia tárolt teljes vér koaguláétöjártak megelőzésére és irtás vizsgálati vagy tárolási mintákban a koaguláció megelőzésére száriért áaszaálbatő, így & találmány szérinti vegyiílstékét bármilyen Xa faktort tartalmazó vagy feltehetően tartalmazó és olyas közegekhez hozzáadhattak vagy azokkal étintkeztetheb jük, amelyekben a vér koagulációjának gátlása kívánatos, például amikor az emlős vérét olyan anyagokkal, mint ét beültetések, lágüók, ortopéd protézisek, koszorúér-tágitók, szívbillentyűk és protézisek, testen kívüli keringető rend szerekkel és hasonlókkal hozzuk érintkezésbe.To prevent coagulation of stored whole blood and to prevent coagulation in stored test or storage specimens, the anti-coagulant therapy is intended to include any factor Xa that may or may not be added to such media, e.g. contacting the mammalian blood with materials such as implants, soft tissues, orthopedic prostheses, coronary vasodilators, cardiac valves and prostheses, extracorporeal circulatory systems, and the like.
PéldákExamples
I, PéldaI, Example
N-(ő-Br6sn-2-t;iridinsÍt2í4-atnÍ3Í3«ete»dkarh<m3feioim>tfeo{ikarhuzii»ttdN- (O-Br6sn-2; iridinsÍt2í4-atnÍ3Í3 "ETC" dkarh <m3feioim> {tfeo ikarhuzii »ttd
292 mg (1 mmol, I ekvivalens} N-t S-brbm-2'píridlndt-2-amin<;feniik&rb«sitmld, tóS mg (1 ekvivalens} 4-ciariobenzoii-kioriá, 3 ml piridin és 10 mi diklórmetán elegyét i éjszakáé át szobahőmérsékleten keverjük, maid vízzel mossuk. A szerves réteget ntagnéziurtt-szulíáton szárítjuk, szűrjük és bepároijuk, Így }49 mg Í?Ö %i N (á-bíom·?-put4mirt<n4.<um,di,>ndksrhomíetn?noneutíkubn\miidot kapunk. MS Cj.dbdárNóbj (M; Bt2421.A mixture of 292 mg (1 mmol, I equivalent) of Nt S -brom-2'-pyridyl-ind-2-amine; phenylmodil (1 equivalent) in 4-cyanobenzoyl chloride, 3 mL of pyridine and 10 mL of dichloromethane overnight The organic layer was dried over N 2 O, filtered, and evaporated to give 49 mg of N, N (α-pulp ·? -put4mirt <n4. <um, di,> ndksrhometn? noneutkubn). MS m / e BdbdNobj (M; Bt2421).
ν'! \ xt p \ χ\ ' ' ' ί f ni > ' x vi'ük κ! k->'>, s <>\o \j i U > ?' I 'et'' > υ készük .oldatába 0 ''Crna íslitéslg iddujgéndílörid gáti buborékolbtuak, Az elegyít i épzakéd sí sZísbaidlmérsékiéíea kövöfjült majd bepáröijpk, A képzadöd maradékm 4ö mg aftmiómummeetémd és lö mj metamdisl 2 θ’··»} at !<'<'\üvas k>η';! vad- 1 zuzu ax nAekmíeíi ί\..«ι>Μι 'epvokek ?s a ww benzamídiat HPLC sljsrássaí (üí8 idrdlpiít fázis} ÖJ % tdfluometsawt Isdatóazö vizmcataskfd aisggyíö ikobi évii. χ Ί >' ' ' \ m bibi i ' a üdnsh 5 11 ni hKj m ·ϋϋ^!< K}küdke!\i\ r Km kapunk.ν '! \ xt p \ χ \ '''ί f ni>' x v i'ük κ! k ->'>, s <> \ o \ ji U>?' I '''''''''''''''''''''' 0 '''''''''''''''''''''''''''<'\ uvas k>η';! wild- 1 zuzu a x nAekmíeíi ί \ .. «ι> Μι 'epoxies? and ww benzamidate HPLC slides (ü8% iddlp phase) ÖJ% tdfluometsawt This is a vismcataskfd aisggyíö ikobi year. χ Ίd'' 5 11 ni hKj m · ϋϋ ^! <K} yell ! \ I \ r Km we get.
2-3 L Példa2-3 L Example
A 2-31, példa szériád yegyüleíekeí az 1. példában leié egáidssid sHiimk plö.The compounds of the series of Examples 2-31 in Example 1 are the compounds of Example 1.
ni. » wrx'M * fYGX .Hni. »Wrx'M * fYGX .H
4^ , -V ^r) 4 ^, -V ^ r)
B&V v.sN;B&V v .sN;
r ,r,
KV VN u vy v;·'^ „ ssv,J »»' Xs-M^.,9.^,,··^ a !? 5 öay-XMKV VN u vy v; · '^ „ss v , J» »' Xs-M ^., 9. ^ ,, ·· ^ a !? 5 ayay-XM
2.. PéldaExample 2
MS íM-tH): 466MS (M + H) +: 466
IX,IX,
3, Példa ' .:VS,Example 3: VS,
4. PéldaExample 4
s. Példa.s. Example.
MS (M Hl):MS (MH +):
M.S {MA®: 508M.S {MA®: 508
MS <M·®}: 494 güMS <M · ®}: 494 g
Í-sepg.I-SEPG.
K’v.-íXv, ,r •«a e g'-. ;; K'v.-íXv,, r • «ae g'-. ;;
VíSAv κ-·Ά%.VíSAv κ- · Ά%.
K > ?j m \·χ· ^U·' '?/ ''Λ w '•x-jsA. ^.-.·Ν\. ...s^v li g j '’tftjAs»’ s'·· « xxK>? Jm \ · χ · ^ U · ''? / '' Λ w '• x-jsA. ^ .-. · Ν \. ... s ^ v li gj '' tftjAs »' s ' ··« xx
c.c.
'V«%·%'V'% ·%
A.X„ >. Példa MS (M-H).A.X ">. Example MS (M-H).
·? Sí.;: ··· ::. ί·? Ski;: ··· ::. ί
MS (M + Hp 454MS (M + H + 454)
k. Példak. Example
MS <Mril)MS <Mril)
468 ö Példa468 Example
MS !>·ί·ί·Η1; 49g 'MS!> · Ί · ί · Η1; 49g '
V · |giV · | gi
Μγ-á sΜγ-s s
OöyAtfP Xiy'Xv ‘ «ο^Χ íb .sA. ,^'ζχOöyAtfP Xiy'Xv '«ο ^ Χ íb .sA. , ^ 'Ζχ
Xtxt
Χ·.··γ x-xΧ ·. ·· γ x − x
i.S<j·'·· ifl5xxiS <j · '·· ifl5 xx
10. PéldaExample 10
MS CM Md). 506 ί I. PéldaMS CM Md). 506 Example I
MS íM-í'Pj): 506MS (M + H) (PI): 506
12, PéldaExample 12
MS (M X): S241MS (M +): S241
13. PéldaExample 13
MS (ΜΑΗ}:. 524MS (+): 524
Η)Η)
14. PéldaExample 14
US (jMdll);US (jMdll);
$21 ,s-· Xg,,$ 21, s- · Xg ,,
FF
ΥΥ α rYnrn * γύυυ * x»*yy^ g i VSxMfc. A-·' kA^...-m,,··ΥΥ α rYnrn * γύυυ * x »* yy ^ g i VSxMfc. A- · 'kA ^ ...- m ,, ··
Y '< Ί Ay-MM **08. MA.Y '<Ί Ay-MM ** 08. TODAY.
T ΪΊT ΪΊ
OeusA^ vxOeusA ^ vx
Z Ys 5 Ay“Y \A«Z Ys 5 Ay “Y \ A«
15. PéldaExample 15
PéldaExample
17. Iklda17. Iklda
MS (M HI);MS (M + H);
S07S07
MS (M'Hl):MS (MH +):
476476
MS (M+«); 480MS (M + -); 480
Rá { Ύ y r 4 ? í Y Jt, .-x Α» ην^.Α.-’ν v'· Xí V*V t 4 A ;l„ il JOn it {Ύ yr 4? í Y Jt,.-x Α »ην ^ .Α .- 'ν v ' · Xí V * V t 4 A; l„ il J
Wv,Wv,
ΑΓΥΥ «ΑΓΥΥ «
C,O χγγ -γη g <5yU <·.>».-- xvXYC, O χγγ -γη g <5yU <·.> ».-- xvXY
Y-3?'· ’Ά (X.Y-3? '·' Ά (X.
18. PéldaExample 18
IP, PéldaIP, Example
20, Példa20, Example
11. PéldaExample 11
MS (Mőft 47?MS (Moore 47?
MS(MÜi):MS (MUI):
463463
MS (MMJ:MS (MMJ:
MSÍMMOMSÍMMO
Χχ<ζ''^ν'·''Υγ a ΐ m *<w &»/ Wy*. y-m>,Χ χ <ζ '' ^ ν '·''Υγ a ΐ m * <w & »/ Wy *. ym>,
XrYXRY
V'· '£íV '·' £ í
Rá iX-t-x ö?' U tXAC IX-tx uh? ' U tXA C
Χ,ΙΥ «<yX'! XΧ, ΙΥ «<yX ' ! X
Χ ’%Χ '%
Y.A xsÁ'iY.A xsÁ'i
Is '1Is' 1
12. PéldaExample 12
MS (M PH}: 464MS (M + H): 464
25. PéldaExample 25
MS (Mi'H): 410MS (M + H): 410
24. PéldaExample 24
55. PéldaExample 55
MS tMl H): 462 ij'R .A,,.'u.MS tMl H): 462 ij'R .A ,,. 'U.
««W Y A fií-á ’Ύό *·· «γΧ*· ΐΐ?·ί.χ ,.·ίγ.«« WYA fií-á 'Ύό * ·· «γΧ * · ΐΐ? · Ί. χ ,. · ίγ.
yy í€,...yyy í €, ... y
VJ t nVJ t n
Y*Y ‘>\ \!Y * Y '> \ \!
. Példa. Example
28. PéldaExample 28
24, PéldaExample 24
MS (MH1): 408 MS (M*H): 25 MS (MHi): 450 (MtiH}: 462MS (MH +): 408 MS (M + H): 25 MS (MH +): 450 (M + H): 462
1-Η}.' 394 MS (Μ).491Η-1}. ' 394 MS (Μ) .491
32, Példa32, Example
N.í6-Pró«i-2-piridbdbd-;4-i2-bnid8zöibdl}bíndk8rboad3ndnoilVsdfe»í'bosgUíkiN.í6-Pro "i2 piridbdbd-; 4-i2-bnid8zöibdl bíndk8rboad3ndnoilVsdfe}» í'bosgUíki
mg ;t>2 mmoi)N-(5-bróm-'2-pirldinilp2-{4<iata>il!ín{lk5uboni{amjno)ft;nl!karboxamid 5 ml metanollal készüliohksuhs fi ’M'-ös selbmg bldrogán-klödd gázt buhoráköttatunk. Az -elegyet 1 éjszakán át szobahőmérsékleteit követjük» majd feepáföíjnfc. A visszamaradd anyaga; 4Ö mg.etil'éo-dlamlnoál Ifi ml metanolban 3 -órán .át > ’.vutóAi'Sis di’K'n 'os .íÍío, ϊ .mán at ddt's.ra; .Λ. n.n k'pánnu»k. es λ mö' Ι\λμ nahát ; < i o 1 < A Λ dán .'M't \ >8*1 h,K<·,;·.tratuitl·? > <ra cr I dra. <-x .>rara \ üi.k, így 41 mg {§9 %} N-<'S-bfőm-3-nlridmilj“2-[4-{24midazollnill feoilkarbomlammojfeniikarböxamklöt kapunk, MS C£;Hj<,SfNA. #<: 464,mg; t> 2 mmol) N- (5-bromo-2-pyridinyl) -2- (4-methylthio) -cyclone (amino) -phenyl] -carboxamide with 5 ml of methanol was prepared in M 'selbmg bldrogan- blast gas. The mixture was monitored overnight at room temperature and then overnight. Material of the remnant; 4 mg mg of ethyl'eo-dlamlnoal Ifi in ml of methanol for 3 hours .at>'.'Ais'Sisdi'K'n' os., 10, at ddt's.ra; .Λ. nn k'pánnu »k. es λ mö 'Ι \ λμ leather; <io 1 <A Λ dán .'M't \> 8 * 1 h, K <·,; · .tratuitl ·? ><ra cr I dra. <tb>xxr> rara, yielding 41 mg of {§9%} N - [(S) -bromo-3-ylmethyl] -2- [4- {24-imidazolenyl-phenylcarbomlammoyl-phenylcarboxyl], MS C £ ; # <: 464,
31-41, Példa31-41, Example
A 3.3-41. példa szerinti vegyieteket a 32, példában leirt eljárással állítjuk efő.A 3.3-41. The compounds of Examples 1 to 6 are prepared by the procedure described in Example 32.
O f ϊ a-AdM Η'' ΧΉ eXO f ϊ a-AdM Η '' ΧΉ eX
......
ο<>>.-··Ήί-·· ¥πο <>> .- ·· Ήί- ·· ¥ π
V>>- 'g.V >> - 'g.
W il,. Aj ' U^·' v·'·W il,. Aj 'U ^ ·' v · '·
LLLL
S.SS-fcS.SS-fc
PéldaExample
MS íM'BI): 4'ΜMS (MH +): 4 '
34. PéldaExample 34
MS <M4H): 492MS (M + H): 492
35. Példa í'M Hh: 4?SExample 35 1 HM: 4?
Ax'$s'The x '$ s'
Ά'Λ ·' •ArS·*] ix x*·'Ά'Λ · '• ArS · *] ix x * ·'
3$. ÍWa$ 3. IWA
MS (M-i-K): 493 z aMS (M-i-K): 493 z a
VSdX ** VC χ..·^VSdX ** VC χ .. · ^
Í\-V A’< .·;:·< -•Uv|·· s»‘·Í \ -V A '<. ·;: · <- • Uv | ·· s »' ·
IXIX
CLCL
Y s &5Y s & 5
Is Λ dIs Λ d
XrVA »εγ·ΉXrVA »εγ · Ή
Γ 'ífYeah
Yp- η ΜZ\Yp- η ΜZ \
Ρ Α-4 S ^s··· >4..,η.Ρ Α-4 S ^ s ···> 4 .., η.
g ;·;·g; ·; ·
L\,Af^L \, A f ^
OfSfcA,-*’OfSfcA - * '
v.v.
37. Példa 38, Példa 39. PéldaExample 37 Example 38 Example 39
MS iM-i-B): 434 MS CM-M1}· 4*8 MS (M *K) 434MS iM-i-B): 434 MS CM-M1} · 4 * 8 MS (M * K) 434
40. PéldaExample 40
MS (MAH); 44«MS (MAH); 44 «
41. példaExample 41
43, és 43. PéldaExamples 43 and 43
Β-ΐ5-ΒζΟ^·.2”ρΐί50!«11)·'2·'14-'|1,Ρ'41οχθ'(1ί4'44ϊζ»ρ«Γ0ή1ί'θίϊΖ'·4'·!ΐ}1κ!ί!5θ5η®Ιΐ1Β«ίί111ί3,η1)ορ1|3ηίίη?>1'· feadka rbova sn irf ésΒ-ΐ5-ΒζΟ ^ · .2 "ρΐί50!« 11) · '2 · '14 -' | 1, 41'41οχθ '(1 ί 4'44ϊζ "ρ« Γ0ή1ί'θίϊΖ' · 4 '·! Ϊ́} 1κ! Ί! 5θ5η®Ιΐ1Β «ίί111ί3, η1) ορ1 | 3ηίίη?> 1 '· feadka rbova sn irf and
N-(5-bröín-2-pjrkl<5í8l.}2-|4|í~oxO”i'} ,4-1 laza peíhkfrosn-'MO*N- (5-bromo-2-pyrrole <5,8l.
IsfífeomeM Hé a II Is ar bo a jlamlso) fed il lösr bex sas álIsfífeomeM Hey a II Is ar bo a jlamlso) fed il lösr bex sas mock
mg (ϋ,Ι mmól) pd-tiazninírluifeoinM-djindoöinetdjisstllk&rhönd'atnhrol fenilk&fbox&tnid és 3 snl 30 %-os; hidíogén-peres ál elegyét szobahömérMk.ieten 12 órát; át keverjük, kantán sziláid náúáonpdosaólldí hozzáadásával. moghdhtjüH· AZ anyagot HPLC kijárással (Cl 8 iosdüöti iáais) 0,5% tnöttotecétsavat tartalmazó víz/aceiomtril eléggyei ehtáiva tisztitjok, így IS mg (31 %) N-é5-bröm-2pirÍdiaii 5-2-14-1II, i-<íioz<r-(l,4dlazaoerhldroát-4--||)inuaootetinísrólkarbonll8noín>}feuiiliai'bnxasnldot (MS C,;:H «CINjÖ<S ÍM-Hk: 512.) és 20 tng (41 %) N<5-bröm-2-pirldintl}*2-{4*(l'OXö*{U4-ttazaperhtdro«H'‘ ni)lnutmmatíljfenilkarbotúismmíí)tnnilk&ffeoxsandot [MS 'Cj^-HsaCiNaOjS (Ms-jd)· 1 40b] kapnak,mg (ϋ, Ι mmol) of pd-thiazinine fluoro-M-djindo-ethanol-dinyl-phenyl < - > hydrogen pellet mixture at room temperature for 12 hours; stirring with the addition of cantane solid. The material was purified by HPLC (C18) using 0.5% water / acetylmitrile containing enough ethyl acetate to give IS mg (31%) N-? 5-bromo-2-pyridyl 5-2-14-1II, i- < íioz <r- (l-4-- 4dlazaoerhldroát ||) inuaootetinísrólkarbonll8noín>} feuiiliai'bnxasnldot (MS for C,; H «Cinja <im S-Hk: 512) and 20 tng (41%) of N <5 bromo-2-pyridine} 2- {4 * (1'OX6 * {U4-thtazaperhthro ("H '')) mutylmethylphenylcarbotylsmall) (MS 'C13H8ClNaO3S (Ms-jd), 1440b)
44-49. Példa44-49. Example
A következő vegyöíeíéket az 1. és 32. példában leld eljárással állójuk elő.The following compounds were prepared by the procedure of Examples 1 and 32.
PaóksPaóks
MS (M-i-H): 4?4 l\daMS (M-1-H): 4-4
MS 502MS 502
46. Pékin46. Baker
4'·’ Petii s4 '·' Petii s
MS (M-t-H): 400 MS {M+H}: 514MS (M-t-H): 400 MS (M + H): 514
4b. Pólás4b. Polasek
40. Példa fok HldnExample 40 degrees Hldn
MNMN
5. Lépes ' '8 n g t Ό s o1 ’ em k ' Λιρ' éu ' m u ' 1 ue ’< ,»'? a Αχ d o d uzhm ’b d no i' ni (5.05 msuo!) 0,5 mólos tolaolos káikutt-hlszíísátoedíszhiljíaitidot esepegtettufo, Ezntásr az, elegyet még ÍZ,5 érés át .·.·.·?§ ®í>öíí keverjük, majd ugyarrezeír a Ikhnérsőklctso 0,5 g (2,55' mmoi) Afolörtzatlnsav'anhldfidet adónk, hozzá. A képződött elegyet fokozatosan szobahőmérsékletre melegítjük és I éjszakán ál keverjük. Ezután telített vizes .ammóníonkklorld-oidattaí iueghörajnR:, és etibaaetáttai eéttábáljdli. A szerves téteget itragífoziürü·szulfáton száritjuk és bepároljuk. Így 0,7! g pOösfo {2-ammoö-klórfonií>N-f5-któT«25psridiO-karboxamidot kapunk. MS C!?HsCÍjN,O M*-~ 282, (Mt-2f-284.5. Steps''8 ngt Ό s o1' em k 'Λιρ' éu 'mu' 1 ue '<, »'? uz dod uzhm 'bd no i' ni (5.05 msuo!) 0.5 molar toluoyl-caicutylisolateo-esylacetyled espegtettufo, To this end, the mixture is tasted 5 more. ·. ·. ·? § ®í> oi 0.5 g (2.55 'mmoles) of Afolorzatlnsic acid anhydride is added. The resulting mixture was gradually warmed to room temperature and stirred overnight. Then, saturated aqueous ammonium chloride solution was added and diethyl ether was added. The organic layer was dried over itragiphosulfuryl sulfate and evaporated. That's 0.7! g of psoSfo {2-ammono-chlorophonyl] -N-η 5 -tetrahydro-carboxamide is obtained. MS C !? H s C 1 N, OM * - ~ 282, (Mt-2f-284.
2, tépés .0,71 g (2,52· tömői) {2-mnlno-5-kiórfeml>-N-íS-klór-2-p5rid«l-k8rboxamid lö tói á'iklórmetáfínaí készült <. kx Utó 3 ’ i C '·’ omol> ' , , > ohrm ' \ > s., < « n, 1 ' s> , 5 \« t ot' dr t udts 5» A képiedet elegyet 1 éjszakást át szobsshdmétsékiesest keverjék. A kivált csapadékot kiszürpik es dsk les'sm-tasmsti mossuk. tgy 855 mg (66%) Nd4*kfo?-24NA5*któr-2-pináil)karbíanosljfenlU-(4«cianoi'eml')kart>oxttjnt0ot kapunk szdárd anyag alakjában. M 8 ί.\χΝ -A? L tg,.') > ki -í í 1.1 Iv?: g.? ·: 015,0.71 g (2.52% v / v) of the {2-methylno-5-chloromethyl-N-S-chloro-2-pyridyl-1-c8 -boxamide extractor was prepared from methyl chloroformate. kx After 3 'i C'''omol>',,>ohrm'\> s., <«n, 1 's> , 5 \« t ot' dr t udts 5 »Stir your mixture for 1 night at room temperature . The precipitate is filtered off and washed with dsk les'sm-tasmsti. Thus, 855 mg (66%) of Nd 4 - [[alpha] - [beta] N-5 [beta] -chloro-2-pinyl) -carbanoyl] -phenyl (4 cyanoemyl) -acetamide are obtained in the form of a crude material. M 8 ί. \ ΧΝ -A? L tg,. ')> Who -í 1.1 1.1 Iv? : g.? · : 015,
5, LépésStep 5
683 nig (1,66 mmoi) Ng4-kldr-2-(N-4fokiór-25slndtlK3rhamö{l.jfemlH^-cmm>feoil)karb<«samid lö tol sízmentes pordumel es t ml p-íeohrmmra? kes-mli otdstát 0 'í\m Smh-ogen-x-mfod gazztl tebtrük Az etegyet t éjszakái? át szobahőmérsékleten keverjük. I3z«ján· az öldészeN iepátolj??-k, és a marasiékot 5 rsd vízmentes acélosban. oldjuk, majd az oldathoz 1 ml (Í6,é mmólj.jődmmánt adunk hozzá. Az elegyet 2 órás ás keverés és viszr 'erőhatás kö’beu fen,ríjuk Pentán ez oldószert lep.tr,'kuk, es .? truunookot * mt vs.unemes metanolban okbuk, az oldathoz 0,732 ml (8,5 mmoi,! N-rf-etiteiléndiamÜ! és 1.5.mi eeetsav 5 üü vizméntés metanollal készült oldrttát adjuk. Az elegyet keverés és visszafolyatás közben 2 órán átforraljuk. Ezután az oldószert íepároljuk, és a nyers maradékot RK>HPI.C eljárással tisztítják, így N-{4-kiö;s2-[M-(5-l<forfo->piridink;rfb;ns?öíÍ]leídlj [4-( 1 --ÍnethÁhfodazölfoxifolliérdl}káfboxiümdíst kapunk fehér por .alakjában, MS ÁiHieCbNsÖj MM68 (M ?2r : -1?«).683 nig (1.66 mmol) NG4 kldr-2- (N-4fokiór 25slndtlK3rhamö l.jfemlH {^ - c mm> feoil) carboxylate < «Samid lÖ tol sízmentes pordumel ml and p-íeohrmmra? who-m-otta-stats 0 'm Smh-ogen-x-mfod gazztl tebtruk Do you eat food t nights? stirring at room temperature. I3z «j» the killer is gnawing and marasille in 5 rsd anhydrous steel. After stirring for 2 hours, stirring and refluxing, the solvent was pentane-tr, -uk, and? truunookot * mt vs. Oxybutane in methanol was added, and a solution of 0.732 ml (8.5 mmol) of N, N-ethylenediamine and 1.5 ml of acetic acid in 5 ml of water and methanol was added to the solution. The mixture was stirred and refluxed for 2 hours. and the crude residue is purified by the procedure RK> HPI.C to give N- {4-chloro; s2- [M- (5-1-phosphorus] pyridine; rfb; nsulfinyl)] [4- (1-dimethylphosphazole)] } a coffee powder is obtained in the form of a white powder, MS AliHieCbNsÖj MM68 (M? 2r : -1?).
55-75. Példa55-75. Example
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76, Példa /'-b < <76, Example / '- b <<
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NMNM
L t.epés i y m ' n nn-b ' n-et . mü-mcnvesa. ' mi dó iramúimmá kévéit otduiAt » (MM nd i SpM n,n >7' oxalll-kkn-kloi és néhány esepp dimetilformao-»ldoi adunk. Az elegyes 2 órán ál szobahőmérsékleten keverjük, ' Μ i rabra e.vn. h i\ 'vat'i.Ww < χ mlM unté Ίνη o dj tk v,nht\i, K ! iram? wlV ••arnnío-5-kiőrpiridürt só 1,34 ml, 116,56 mn-oll piriüini adunk. Az Megyei 1 éjszakán ál szobahőmérsékleten keverjük. Ezután az oldószert lepároljuk, és a «vers maradékot szilikagéioszíopon 25 % etil-acetátot tartalmazó \rara' i ,k 2' ,t boo ram. diósra' < v m 18 o <9 < ' 4 \ r \t,,f < p{ 1 V i\ d ' m. ek'miXvtmámidőt kapunk, MS C^íjfi^iKÁ MWl, (Μ-Μ)'Μ<Μ,L t.epés iym 'n nn-b' n-et. False-mcnvesa. "we add the fastest shaking otduiAt" (MM n di SpM n , n > 7 'oxalyl-kkn-chloro and a few esepp of dimethylformaol). The mixture is stirred for 2 hours at room temperature, "r i rabra e.vn. hi \ 'vat'i.Ww <χ mlM unté Ίνη o dj tk v, nht \ i, K ! rate ? wlV •• arnnio-5-chloropyridine salt 1.34 ml, 116.56 mn-ol pyridine are added. stirred at room temperature overnight. the solvent was evaporated, and \ RARA the "verse residue with 25% ethyl acetate, silica gel column, 'i, k 2', t boo ram. DIOS '<vm 18 p <9 <' 4 \ r \ t ,, f <p { 1 V i \ d 'm. ek'miXvtmam time is obtained, MS C ^ ffi ^ iKÁ MWl, (Μ-Μ)' Μ <Μ,
LépésStep
1,48 gt'5,1 mmol'iN'LS-kíórC-puidil'kS-meiikl'nitrofeníljksuboxamid 10 ml metanollal készüli old&iáhz 1,46 g (öj9 mmoi; 5 %-ös szénhoruözPs platinn -katalizátort: .adunk. Az elegyes bidr&géübálloa alatt 2 őrén ál szofeMéínőrséklstéü kévérjők, Azután CnSiíe rétegen átszűrjük, a szörletel bepároljuk, Így 1,56 g (166 táj (2“amino-5-meiiltenilj-N-i k-pirldilikarbownidot kapunk. MS CsjH -CIN?06-0-262, (M+2Γ -264.1.48 g (5.1 mmol) of N'LS-chloro-C-pyridyl-5S-methylnitrophenylsuboxamide are dissolved in 10 ml of methanol, and 1.46 g (9 mmol) of 5% PBS is added. add the hydrogen under & géübálloa 2 Oren at szofeMéínőrséklstéü mix, then filtered through a pad CnSiíe, szörletel concentrated to give 1.56 g (166 scenery (2 "amino-5-meiiltenilj k-Ni-C and MS pirldilikarbownidot obtained jH zinc.? 06-0 -262, (M + 2Γ -264.
3. LépésStep 3
1,36 g (5,2 mmo.lj-(2-amíno-5-metlttenii}~N'-(5-klóf-2’pifidiljkarbox3míá 10 ml diktőnsetóonal készült oldatához k6ö m,g (5.3 uüsöí) 3<.íauöbeuzölí-klortdot és 1,26 ml. (15,6 mmoi) psridini aduhk. A reakesöeiegyet szobahöiPérsékleien i éjszakán 'át keverjük. jszuiau áz oldószert;' lepároljuk, és a nyers maradékot sztlikagáloszloíMu 25 % etll-aéeiátnt i&pnlistázó hexántiai élűéivé ijszfitjuk, (gy 820 mg (43 %} M-(2-(bl-(5-ki6t-2»ptridit}karbamo}tj-4-medhendi{4-elanoíeniÖkarlx)X3mídoi kapunk szilárd anyag: alakjában.· MS CsjR^CIRjOf M' -390,To a solution of 1.36 g (5.2 mmol of l- (2-amino-5-methylenethyl) -N '- (5-chloro-2'-pipiphidyl) carboxylic acid in 10 ml of dictation line, k6 m, g (5.3 µL) of 3 µL was added. chloroform and 1.26 ml (15.6 mmol) of psridine adduct. The reaction mixture was stirred at room temperature overnight. 820 mg (43%) of M- (2- (b1- (5-methyl-2'-pyridite) carbamoyl) -4-medahydroxy-4-ethylenecarboxyl) are obtained in the form of a solid. 390
4, LépésStep 4
830 mg (2,1 mmölj 1S-(2-(7l-(S-kÍ6L'3-píríd6)karb;püóíl]-4-iH8til!euilí(4'Máno1bníi}karbósámid 5 ml s p\ üés C«tt'tbi>s t 'le ^erai . ' Sk -ί- i ,si 0 < un Mueran \ί.κκ ρ,α'νΐ iélst ti\ ^rade s. 1 éjszakán át szobaböinérséklelen iíev«jiik2Bz;u!án az oldószert lüpáspljuk, és a rnaradéjíof 5 snl vizinenies rsstanolban. oldjuk, majd az oldathoz 6,620 ml (16,5 mmoi) M-irsetileí iléndlamlnt adunk. Az elegyet 2 Órán át keverés és s ssx ♦ \b ϊ „ k 0 'Ti Vs , *ra > ' om>„ i|»m« av <- a ovem n aradékut - RP-HPLC eljárással pszOijnk, igy N-(:2--fN--(5--k|pL2MÓtdil)karbamoiiJ-4-n-íeti||bntlj (4-(l-metil-2-(l{«líl8Zö.bn-z-íl}dtsní|.}karboxsmidot-kapunk fehér por alakjában, MS CpHrt^lHtQs M'-448, (M'L2f :-;45ö,830 mg (2.1 mmol) of 1S- (2- (7'- (S-chloro-6'-pyrid6) carboxyphenyl) -4-1H-8-yl-ethyl (4'-mono-phenyl) carboxamide in 5 ml of a solution of C > st 'le ^ erai.' Sk -ί- i, si 0 <un Mueran \ ί.κκ ρ, α'νΐ lives on ti 1 night, at room temperature, the solvent is evaporated, and dissolve in 5 snl of aqueous rsstanol, then add 6,620 ml (16.5 mmol) of M-irsethylene ethylene dbl, stirring for 2 hours and s s x ♦ \ b ϊ k 0 'Ti V s, * " om > m < - > - we overexpress the RPM-HPLC to yield N - (: 2 - N - (5 - [mu] m 2 -dimethyl) carbamoyl) -4-n-yl. bntlj (4- (1-methyl-2- (1 - {[l8] 8Zl.bn-2-yl) dinyl) carboxamide is obtained in the form of a white powder, MS CpHrtlHlQs M'-448, (M'L2f : -; 45 °,
77-82, Példa . <km '0 \lb'ra ι.> 1 s sí n-ral < íbp,!'-< <377-82, Example. <km '0 \ lb'ra ι.> 1 s with ski n <íbp,!' - <<3
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79. Fáim;.79. My Trees ;.
86. PéldaExample 86
SL Példa S2, PéldaSL Example S2, Example
L LépásL Step
0,3' g (R9S tmítöl) 2s4Á'4r:in«tösiALniiröbenzoesav 5 tnl dlktőrmeiámiid készük oldatához 0,34 ml (Á9 mmöi) ósául-klörldoi és néhány csepp d;mehííörünüo.ldot: adunk. A reakcióé legyét szZihahomérséklsten 2 <. , η λ \ > Ux ni xh !x \sfxi sok , > m ) , xi.'ko, χ η ηκ y n 15 i ei > e, L χ !xi< t ./Úü <' (4,7 πηιιοί.ι IxándnOxAbíősnplrÍdhg és 0.94 mi (ii1,7 mmoi) pü’láint adunk. Az. elegyet 1 éjszakán át xsebséernérsékleten keverjük. Bzelán az oldószert letároljuk, és a nyers ínaradéhrb szdikagéiöszlopun kroma.togrtófósa» tisztítjuk, eíaálészetként 25 % etikaeetátet tartalmazó hexánt használunk, így 790 mg (08 70} N-(SxláÓ!p--2-pHSíiil)(3.4,5xtísH!etexí-2-pítrofentWsíbox;n-fiítkd: kapónk szilárd .anyag alákjAé55, MS CtsH.HÖrNjOs MM:2, t ML?.} 414.To 0.3 g (R9 S) of 2 sec 4'4r of crude allylbenzoic acid in 5 ml of dichloromethane amide is added 0.34 ml (9 mmoles) of asl-chlorodol and a few drops of dichloromethane. The reaction was mildly 2 <. , η λ \> Ux ni xh! x \ sfxi sok,> m), xi.'ko, χ η η κ yn 15 i ei> e, L χ! xi <t ./Úü <'(4,7 πηιιοί The mixture was stirred and refluxed overnight. Thus, 790 mg (0870) of N- (Sxla-p-2-pHSilyl) (3.4,5xis-ethyl-2-pyrrophenyl) -filtrate: is obtained as a solid, 55% , MS: ML?.} 414.
2, LépésStep 2
790 mg (1.92 mmoí) N~(5~brösa-2~pÍBdiní3A5-trbr>et0xi'2-nhroíenlbkart>ox3?nsd 5 mi ebbaeetátial készük oldatához L73 g (?,Ó7 műtői) öriílükiorid-hidrátö; adunk. Az elegyet 2: órán át keverés és visszafölytbás kodiei tenniük. Ezután Leibe rétegen átszűrjük, a széklethez. IN nátrhnn-hidroxsd'Oldatot adunk és eíti.acetaue! extranáljuk. A szerves rétegei magnézitsmmzidkkoii szúrniuk és hspáiPjjuk, így S70 mg (77 70} (2-amíso-.Ld.bdrtn'tetoxifenlii-N'iü-hAhn-z-ph'idÍljkarboxamidei kapunk, MS C^H^StHAs MMS2, (M'f'2 ) :::3 k4,To a solution of 790 mg (1.92 mmol) of N- (5-bromo-2-piperidin-3A5-trb) ethoxy-2-nitrobenzene> ox3? Nsd in 5 ml of ebebetate was added L73 g (0.7 mmol) of aryl chloride hydrate. After stirring for 1 hour and refluxing, it is then filtered through a Leibe layer, stool is added, 1N sodium hydroxide solution is added and the mixture is extracted with acetone. The organic layers are magnesium hydroxide injected and shaken (70 mg). -Ld.bdrtn'tetoxyphenyl-N'i-hAhn-z-ph'idylcarboxamide was obtained, MS C 24 H 30 StHAs MMS 2, (M 1 F 2) ::: 3 k 4,
3, .LépésStep 3
570 mg < 1,49 rnmol) (3-ζίηίηο··3,4.5 -írtmetosifenii,)-N {5-hr6m-2 -pirid!l)katbosafnid 5 ml diklótmetáunal készült oldatához 247 mg (1,49 minői) /l-ebmobeazcébkÍoridoi és 0,362 ml (4,48 nunol) pináim adunk. Az elegyet 1 éiszákáo át ssohahöntéi'sékleten Ixevétjük, Beátáit az öidószert lepárelíuk, és a 'nyers maradékot . zmimgcios/lopoe .0 '' - etd-arenam tarmáoeze hevunuat ehwt\.j l'remomogr,siesse eszdoak, igy r<80 nigit'Ofei E-í6-(NA5”brém”7-pir!dd)karbaisn?dj-2,3,4.-iriaietozdéed}t4.-eiasxsiéml}karbi>xahddot kapunk szilárd anyag alakjában, MS C,d i><3rN<ö?. M -I 1, báb 2;'-5 12,570 mg <1.49 rnmol) (3-ζίηίηο ·· 3,4.5-rhodomethosifenyl) - N (5-hr6m-2-pyrid! L) solution of cathbosafnide in 5 mL dichloromethane 247 mg (1.49 rpm) / l -ebmobeazebeb chloride and 0.362 ml (4.48 nunol) of pin were added. The mixture was stirred at reflux for 1 h, the solvent was evaporated and the crude residue was evaporated. zmimgcios / lopoe .0 '' - etd-arenam tarmáoeze hevunuat ehwt \ .j l'remomogr, siesse eszdoak, so r <80 nigit'Ofei E-í6- (NA5 'Brem' 7-pir! dd) carbaisn? dj- 2,3,4-iryladophthalate} t.4.alpha.-isoxymethylcarboxylate is obtained in the form of a solid, MS C, di . . M-I 1, puppet 2; '- 5 12,
4, Lápás 'Ά> u J '> n \ í \ >n (\ η ' > s ' ?! ' \í \r ! '' xU'teU'síR ti', > s uiwi Kas nos amid 5 m; vízmentes metanollal és iö ml étii-aeetáttai készült oldatát 0 C-on hidrogén-klorid gázzal telOpik. Az. elegyet szobahőmérsékleten 1 éjszakáa át bevesjéL Ezxstáh az -oldószert: lepároljstk, és s maradéisot 5 ml vérmest' les wtsnolban mldiek. maid az oldathoz 03 Ső tni sb,bS ásnád) N-istetifetilérsdlahtistt adusb. .Az elegyet 2 érán át keverés és visazsafelyatás kbzbon forralják. Ezután ez oldószert iepársdjok, és a nyers maradékot PP-HPLC éljátásssl tsszsüjssk, igy 240 reg (32 %s N-(S-fN-íS-brötn-2“pir}dti)karbatnojlj-2,3,4-ttúnetoxHenl.i) (4-(I-metil-2-(imidazöbü-2-sÍ)]téáÍi}kárboxamido5 kapaftk fehér por alakjában. MS.C^íl^ökNáiöá ΙνΓ:::568, (M-r2i'-S70,4, Lápás 'Ά> u J'> n \ í \> n {\ η '>s'?!'\ Í \ r ! ''XU'teU'síRti',> s uiwi Kas nos amid 5 m; a solution of anhydrous methanol and 1 mL of diethyl acetate is filled with hydrogen chloride gas at 0 C. After stirring at room temperature overnight, the solvent is evaporated and the residue is dissolved in 5 mL of blood. Ső tni sb, bS aásad) N-istetifetylerdlahtistt adusb. .The mixture is refluxed for 2 hours under stirring and reflux. It was then co-solvented and the crude residue was purified by PP-HPLC eluting with 240 reg (32% N- (S-fN-1S-brutn-2'-pyridate)) carbatnoyl-2,3,4-tetroxyethoxyHenyl. ) (4- (I-methyl-2- (2-imidazöbü-Si)]} TEAI kárboxamido5 kapaftk white powder. MS.C ^ yl ^ ökNáiöá ΙνΓ ::: 568, (M-S70-r2i',
44-47. Példa44-47. Example
A kővetkező vegyületeket a 83, példában leírt eljárással állitiok elő:The following compounds were prepared by the procedure described in Example 83:
Og . Ό.Og. Ό.
ö«<ö «<
ejiiaíSs-'r^öjO-xgejiiaíSs-'r ^ Ojo-xg
Ο*«Μβ A g Sí- O'OWS £/Ο * «Μβ A g Ski- O'OWS £ /
46, Példa46, Example
47, Példa47, Example
44, Példa44, Example
85, Példa85, Example
84. PéldaExample 84
N-{2-|A;-(ö-Kiér-2 ~ybfidd}kaHnúéoslp3-immhH-0'fnetsb2-iisddszo?üS'2-8l)feeíijkarböx$3üidN- {2- | A ; - (? -Ker-2 ~ ybfidd} kaHnúéoslp3-immhH-0'fnetsb2-iisddszo? uS'2-8l) feeiijcarböx $ 3üid
ÁiMatii^ii-lH'ciáftófeöiíikarböfsnansifsöltfeféB^kat’bösiíát} előállításaPreparation of AliMati [beta] -1H-cyanophenylcarboxylate]
1,0500 g (éA mmol) 4-eíanobenzoO-kdnrid, EÖOOÖ g (6,4 ntntol) metil-<3-aminoiiofonkarbnxilátX 1 ml (7,0 intno!) trietll-antíh és díklórmetán elegyét szohahöinérsékleien 18 Órán ál keverjük. Ozmán választótölcsér\ tfe , . \ u V ; Í'OSSOS \ et'Cs UH', tkt S 0 U'O SZ, U Ü >í> s t'Opk <. < S,H{bit bepároljak, majd a maradékot sziilkagélnsziopon kromatogralálmk, Igy 1,6548 g (fel %) első szermtl vegyüleset kap«*K x M8 247 (M-m),A mixture of 1.0500 g (AA mmol) of 4-cyanobenzoic acid, 10000 g (6.4 ml) of methyl 3-aminolophonecarboxylate 1 ml (7.0 ml) of triethyl antichloride in dichloromethane was stirred at room temperature for 18 hours. Ottoman Funnel \ tfe,. \ u V; Í'OSSOS \ et'Cs UH ', tkt S 0 U'O SZ, U Ü> í> s t'Opk <. Evaporation of the residue, followed by chromatography on silica gel, yields 1.6548 g (m.p.) of the first product.
Bí pindlükarbsronnll·5-BeadB-t-roaroJeniilkarhosofnidBí Surface Carbonsronnll · 5-BeadB-t-roaroJenyl Carosophos
68.5 mg (0.5 strorol? 2-;a-iisnn-5-kk«'pifidíU! tt,s ml (Ln romolt ülníetilaiunnmüromal reagáktiüná, magi ttro tng vX5 romol· V» tcppsbea ekxtilíroti ütmeket adunk hnzz t. es az etedet azebahóntérsékleteu I8 órán át keverjük:. Ezután a tfünetilalumlnlum feleslegét IN sósavval megbontjuk. A szerven réteget egyesítjük, ntagneziom-sznlfáton ut » <> s vro.....t9...i Íw„.,..>,a\, es o s.ss...n.ro..».iC z.u ι o \ t‘t\t« 2 o>< »»rot ki.rotatoarariíesan üs/t itmk, ro OJ A18 g süO '' ,0 rom ? verni ϊ segroüetro koponl t 8Λ19 5$' jM- ϊ»68.5 mg (0.5 strorol-2; a-iisnn-5-kk) 'pifidil, s ml (Ln degraded to methyl ethyl neomyromal reaction, magt ttro tng vX5 romol · V »tcppsbea extraction rate added to the diet and diet). Stir for 1 hour. s.ss ... n.ro .. ». iC zu ι o \ t't \ t« 2 o> <»» rot ki.rotatoarariíesan üs / t itmk, ro OJ A18 g süO '', 0 rom? verni ϊ segroüetro koponl t 8Λ19 5 $ 'jM- ϊ »
A 88. példa szerinti vegyület előállításaPreparation of Example 88
0,1528 g f’0.4 mmol) B) lejtésben elöállliori terméket IrólRA-tin-ktro nklai tebtrot etanoiban sznbabnroét' sékletén 18 órán át keverünk, Az öidószett iergokérAtlekben .leporoljuk, es a nyers alapú 2 tnl Nmiettletíléndiaminnal 2 órán át, azaz a reakció teljes végbemeuztcietg reoyottntjok Λ végterméket preparadv HP.bC őíiMsW OúAirjük, így 0.1532 g (88 %) etm szerinti vegyűletet kapunk. EiS-Mb 440 (Mii.}·,0.1528 g (0.4 mmol) of slurry product B) is stirred in ethanol in ethanol for 18 hours, evaporated and the crude base is reacted with 2 ml of N-ethylenediamine for 2 hours. The final product was taken up in HPLC to give 0.1532 g (88%) of etm. EiS-Mb 440 (Mii.) ·,
89, Példa (44 (Ditaeüái m btnjsstntomai 11 j fenil j-N- (2 -(N 4 5-klór-2~jró-áliI>áa r ba utol 1-3-t test il jtosr boxé ni álExample 89 (44 (Ditaeylmethylmethylamine) 11 µl of phenyl j-N- (2- (N 4 5 -chloro-2-yloral) 1-3 are added to the body)
A 89. példa szerinti vegyűletet a 88. példa szerinti eljárással állítjokelö, ES-MS 428 i'MM). 90- PéldaExample 89 was prepared by the method of Example 88, ES-MS 428 (1M). 90- Example
44N-{24N-(5-Klór-:2''p!r5dtl.lásrbainöslÍ'-3-tlenil}ksrb8tnöil)fénÍÍksirbósasHÍtÍ44N- {24N- (5-Chloro-: 2''p r5dtl.lásrbainöslÍ'-3-thienyl!} Ksrb8tnöil) fénÍÍksirbósasHÍtÍ
\ m) prl.fe \rortmit wgsu.cte» .t 8't pJO? 'zertatt Jj.rOssal «Httpik ele ΐ% Mis Atr <Μ- 11 91, Példa\ m) prl.fe \ rortmit wgsu.cte ».t 8't pJO? 'zertatt Jj.rOssal «Httpikel ΐ% Mis Atr <Μ- 11 91, Example
N-f 2-|N-(5-KÍÓr“2'ptHdlí)knrbnní<}|ij-3-4ie,niSH4-|isshtö(pip«Hdil)sn«tíf|fant!|kat,boxa«5tdNf 2- | N- (5-KÍÓr “2'ptHdlí) knrbnní <} | ij-3-4ie, niSH4- | isshtö (pip« Hdil) sn «tif | fant! | Kat , boxa« 5td
Α M. példa mrlnü wgyőtetet a:-8R példa szerinti eljárással állíijhlfA. ES-MS468ÍM--H).EXAMPLE M A number of the compounds were prepared according to the procedure of Example -8R. ES-MS468ÍM - H).
92. PéldaExample 92
N-(HK<-ÍS-Kte2- piridsOtebsísnoilj'á'ísessii}(4-1 dsüoígph reikli5di}meütjlenil}kaehows3kiN- (HK <-ÍS-Kte2-pyridineOtebsísnoilj'á'ísessii} (4-1 dsioligphic reqi5di} meütjlenil} kaehows3ki
A 93 példa szerinti vegyületet a 95. példa. szériád etjáoissal átlüjok elő. ES-MS -Idd í M<1).Example 93 was prepared in Example 95. I will outdo your series with etiquettes. ES-MS-Idd (M <1).
93, Példa \'-P iN~sé Kiás' 2-p«ndiEkarbaesoílj-Miends| 4-|md3sotmorí<sU3t-4-sí55srtísiifastsi}kaíboxaaiid93, Example \ '- P iN ~ sé Kiás' 2-p «ndiEkarbaesolil-Miends | 4- | md3sotmorí <sU3t-4-sí55srtísiifastsi} kaíboxaaiid
A 93. példa szezsáts vegYüietei: a 88. példa szerinti eljárással sUlljuk elő, ES-MS 4?ÖExample 93 Sequential Compounds: Prepared according to the procedure of Example 88, ES-MS 4?
94. PéldaExample 94
19-(2-(N-(5-KI:öt'-2-pE'ld|l)ksieb5S5nollI-3-4sedil}:(4-élsoEso-í védlazapeiXdf'oinX önteti Ijfen ö j tehess nt id19- (2- (N- (5-KI: 5'-2-pE'ldI) xyl5S5nollI-3-4sedil) :( 4-Elemental Protective Fluids
A 94. példa szerint! vegyállatét & 88, példa szerinti eljárással álltijtA elő. ES-MS 486 íM-H}.According to Example 94! is prepared according to the procedure of Example 88. ES-MS 486 [M-H].
95, Példa {lM-(Azaperhidröep!hila5n!hain®EI}6ín!lj-N-P''|NA5-feldr~2-pir!dil)lötrbámöilÍ-3-t!«srdjkarb«samidExample 95 {1M- (Azaperhydropyridine-5-hain®EI} 6-yl) -N-P '' | NA5-feldr-2-pyridyl) lithbamoyl-3-ylcarbamamide.
A 95, példa szériád vegyületeí a 88. példa szerint! eljárással állítják alő, ES-MS-482 {MÁI}.Compounds of your Example 95 series as in Example 88! ES-MS-482 {MAY}.
96. PéldaExample 96
A' l24Art5-Kl<n 'á-pn-ídiEkarbasnndP3ttea5h|4Uas5no4.?.'5netilpkrnlkbnjlisn< dl|fead|karbn\amldA 'l24Art5-Kl <n' á-pn-ídiEkarbasnndP3ttea5h | 4Uas5no4.?. '5netilpkrnlkbnjlisn <dl | fead | carbn \ amld
A 96, példa szerinti vegyiPétet a SS példa szerinti élj ásással állítják «16. ES-MS 468 (Μ* I r 97. PéldaThe exemplary chemical pellet of Example 96 is set by the exemplary SS digging «16. ES-MS 468 ([α] D Example 97
19~{2[N-{S~K16f2-pit,tdil}karbamo5l|-6~ii«síd}{4-ymi.ao(sneíila?ntrto}taeíiíjfentljlrarboz5tmÍd19 ~ {2 [N- {S ~ K16f2-pit , tdil} carbamoyl] -6 ~ ii «dd} {4-milli.ao (sndyl? Ndrto} taeilillrarboz5tmID
A 9?, példa szsriötí vegyöletet a 88, példa szerion eliáfáSsai álidjék eiö,Example 9, the Srriotite compound is preceded by Example 88 serion elephants,
88. PéldaExample 88
Ng2-iN-{S~K?óm2>>piHdH)karbamoli|--3’í5e8Ö|HA>}seti^3s4!Sső4eB'abidröpírisHd58^ í i)fe«i i j ka rfoo xanndNg2-iN- {S ~ K? Óm2 >> piHdH) carbamol | --3'í5e8Ö | HA>} seti ^ 3 s 4 ! S s 4 4eB'abidropirisHd58 ^ í i) fe «iij ka rfoo xannd
A 98. példa szérűi!:! végyüléók a 88. példa szériád eljárássá! áldpük élé. dS-MS 414 1M --1),Example 98 Thimbles!:! enders are the procedure of Example 88 series! their blessing. dS-MS 414 1M -1),
99, Példa99, Example
N-’A-jN-f5-Kk'>r-A-piri«!i0ka!-baini)in-drtk'S)idi4-i(Í!Ídr<rtiain!fio)imhmi3wPiileniQkarhíKaasidJN-'A N-f5-Kk '> r-A-pyridine «! I0ka! -Baini) in-drtk'S) idi4-i (Í! IDR <rtiain! Fio) imhmi3wPiileniQkarhíKaasid
A 99, példa szerion vegyíileieí a 88, példa szerinti eljárással áidijok elé. dSAMS 416 (MA ϊ ),Example 99 provides the serion chemical before the procedure of Example 88. dSAMS 416 (MA ϊ),
1ÖÜ, Példa g U-A - j b-jX &idr-Mp;rkhi)kad\inndlj-A' UemhkaiiraismildeüdihninnmeidspírroUdki'é karbonsav1UU, Example g U-A - j b-jX &idr-Mp; rkhi) kad \ inndlj-A 'UemhkaiiraismildeüdihinnmeidspírroUdki'arboxylic acid
A IÖÖ, példa szerűid vegyületet« 83. példa szerinti <Ipuasvd alhtjuk ele BSriMS 498 (Ms-l).EXAMPLE 10 Example IV was treated with <RTIgt; BSriMS 498 </RTI> (Ms-1).
SOS. PéldaSOS. Example
N'l3--|N-(5-Brőtn-3”p5rldO)kaí'isamnii|-3-tleaÓn4-(l-mei:il-2~smidnznOn-'2-ll)íensi|kari'n)xainldN'l3-- | N- (5-Brot-3 'p5rldO) kaí'isamnii | -3-tleaÓn4- (l-meth: yl-2 ~ smidnznOn-'2-yl) equivalents to | kari'n) xainld
' pr rí, \ m '^k\u < Vn ü'W ipi 0 din ekeié »· 8 km 185 V Is'pr rí, \ m' ^ k \ u <Vn ü'W ipi 0 din ekeié »· 8 km 185 V Is
SÖ2, PéldaS2, Example
4“fN--{2-iN(S-B?'ánS'-2-p3ridii)knrbsíiníni|-3'fsend|k8rbaatn0)fenílksrböxa5ntáin4 "f N - {2-IN (S-B-2-ánS' p3ridii?) Knrbsíiníni | -3'fsend | k8rbaatn0) fenílksrböxa5ntáin
A K\? pöda szerinti vegyületet a S8. példa szerint; eljárással állítjuk elő. BS-MS 444 (M-B). Sikk IVidnThe K \? Table 8a. according to example; . BS-MS 444 (M-B). Sik IVidn
Nj2-iNg$-Brótnö-pírs<fíhkaí-hsi»mM-J~tknülI4-unÍ8u(pírr»üdu3Ü}mrtii|tó»üjUarü«!88«5«INj2-Ing $ -Brótnö-PIRS <fíhkaí-hsi »mM, ~ J-tknülI4 unÍ8u (pyrrol» üdu3Ü mrtii} |! Lake »üjUarü« 88 «5« I
A 103. példa szerirsíi vegyOletet a kiC. példa szérimi pljárásaal dPdjyk elé. KS-MSi 494 (MEl). 104, PéldaExample 103 synthesizes the compound from KiC. example with a serum run in front of dPdjyk. KS-MS 494 (ME1). 104, Example
N·|2. d N·ik·d-lróm·-2 gbHdll}ka?baraollj ·.!·danllj{ 4··| bnlí!<dpiperblli}nieldjfanll}karb»sassldF · | 2nd d N · ik · d-lróm · -2 gbHdll} ka? baraollj ·.! · danllj {4 ·· | bnlí! <dpiperblli nieldjfanll}} carboxylate »sassld
A 104. példa szerbéi vegyUkfét a kS. példa szerinti eljárással élbpu.k elé. LS-MS 512 1 Μ* I b lOk, PéldaIn Example 104, the Serbian chemical is described in kS. example in front of edge builder. LS-MS 512 1 Μ * I b lOk, Example
N-{2-jPi--(k-liréíK-2:-pd-bÍJÍ}karbaösöi.ljA“danÍl}{4-4bnlae{jnn}ddila-'4iÍdn«fdjbealÍikarbnxansldN- {2-jPi - (k-learK-2: -pd - bjj}} carbs.ljA "danÍl} {4-4bnlae {jnn} ddila-'4iÍdn« fdjbealÍikarbnxansld
A löd, példa szmbii vagyilleísí a 188, példa szerinti eljárással áliltpik elő. ííS-MP 214 (M+0. 106, PéldaThe example example is described in Example 188. IS-MP 214 (M + 0. 106, Example
N-> í2,jNEC5-Prd?p-2-pis’idd}liarPaaroÍlj-3~desdH4~(laiinoxÓ<4-'l:iszap«rhidroln'-4-fÍÍPiei:d|“ fan 11} ka rfeox&mid N-> t2, jNEC5 Prd-p-2-pis'idd} liarPaaroÍlj desdH4-3 ~ ~ (laiinoxÓ <4-'l: sludge «rhidroln'-4-fÍÍPiei? D |" fan 11 ka} -urea & rfeox
A lOd, példa szerinti vegyülsz a 88.. példa szerinti: eljárással állójuk elő, ES-MS 550 (M-M ). in?. PéldaThe compound of Example 10d is prepared according to the procedure of Example 88: ES-MS 550 (M-M). tendon?. Example
M-(O-8diúx-5--plfi<lj0kísrOíÍ<íSö!li-id ísudl} (4· j tm}«o(pjf5o5MÍiníi}{Hetiijfsni?}k8{fooxa{»idM- (O-8-dix-5 - ppl <lj0krisrOíI <Sö! Li-idsudl} {4 · j tm} «o (pjf5o5Mininii) {Weekly?} K8 {fooxa {» id
A 107. példa szerint! vegyöletsta 88. példa szériád eljárássaldiitdek síd, ESddS 454 (ΜΗ).According to Example 107! Compound Example 88 Your series of process aldehydes, ESddS 454 (ΜΗ).
108, Példa108, Example
N-(3-(N><.S»Klé!r-»2-“is»ridH}8aí'feat»oill-2~<k»Sllf4»(i:-met.0í'2i|saMazöil»“24t)f«»t||3íarfeoxam5dN- {3- (N><. S »Klé! R-» 2- "is» ridH} 8aí'feat »oill-2 ~ <k» Sllf4 »(i : -met.0í'2i | saMazöil» " 24t) f «» t || 3íarfeoxam5d
A 108 peidv! szeriad vegj-ülélet a 88,példa száriad eljárással ájlkjak elő, EE-MS 44(1 (Mti lThe 108 hide! seriad vegj-life by exemplifying the 88-dermal procedure, EE-MS 44 (1 (Mti l
50‘M Hl. i’étdít h-r S-Bremb'airidndiPl-pt-iddrasíaísddiaiiléiídOariasniiiiiíidnaá^-llaöríVídikarOe sasaid N'-(S'-Br6?d~2p!ridi?di)2.-{4-arn!6s!fíöié8íil(ar6ö5diSim,ído>-S“ÓS!e.ídéadkazdexa8!Íd50'M Hl. Feeds Mr S-Bremb'airidndiPl-pt-iddrasidicdidyldilyl O-ariasniilylidid N '- (S'-Br 6? D ~ 2 pyridyl) 2 - {4-arylsilyl. (ar6ö5diSim, time> -S "Os! e.ídéadkazdexa8! oxazolidinecarboxamide
jö9. Példajö9. Example
1. Lépés1st step
L24 g (4 mmol. l,ö ekvivalens) N--(5-btóm--2--pirkim»i)--2“3mfno--5-Ílnorfeníikarboxamkl> 0,792 g (ekvt\Jeau é'KS?a,fo< ívd hfos© t ab pofom <· fo mt sttktonrefon fo,g\et ->','bubómerse!,k'iei' 1 ©vafoin a l.< verjük, Azután az illékony komponensekéi lepároljuk, és a maradékot etll-scetátbaa oldjuk. Az oldatot 1M sósavval, teiiieit vizes •nátrium-hidtogén-karbonál-oklattat és islited vizes sáírknu-kforid-ohífotei mossuk, A szerves rétégét nátriunuszo!laton szárítjuk, szűrjük és bepároíjuk, igy 1,14 g (íks %) N-ffobróni-z-plridintlfikii'· •OÜionkarboaiaíniiiej-S-ilootiertilk&rfeosatitiáot kapónk, MS m/z 4fik (Ma-H) t CjfoiijBrFN.Atí (Mi44)h 939, 44 1,L24 g (4 mmol, 1.5 equivalents) N - (5-bromo-2-pyrimidin-2-yl) -5-fluorophenylcarboxylate > 0.792 g (eq. fo <arc hfos © t ab pofom <· fo mt sttktonrefon fo, g \ et ->',' bubómerse !, k'iei '1 © vafoin a l. <beat, Then evaporate the volatile components, and the residue is ethyl. The solution was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and islited aqueous sulfuric anhydride, and the organic layer was dried over sodium salt, filtered and evaporated to give 1.14 g. -fobronone-z-plridine-1-ylcyclohexyl-1-yl-thiothiolate, MS m / z 4fik (Mon-H) t CjfoloylBrFN.AtI (Mi44) h 939, 441,
2. LépésStep 2
1,12 z (2,56 mmöl, 1 <ö ekvivalens) N A5-brónt--2-pb-ídtnd)A:-(4-cianöiesií lkarbouiííanjftö)''5' -íluorienilkarlxjxamid, 0,2.13 g t 1,2 ekvivalens) hidrosd-ansin-bldstsklöfid, 1. tol éí ietli-amm és 15 ml etil-alkohol elegyét 5b nC-on 1 éjszakán át keverjük. Ezután az illékony komponenseket leporoljuk, és a maradékul élik -aceíáiban okijuk, Az oldatot ÍN sósavval, teiiiofi vizes nátriiKSohídropéíi-kafbonái-oldafial és tel ítélt sozes náiríam-kiorid-oidatiai mossuk, A. swves réteget nátfunn-szufiáton szárítjuk, saátjük és bepótoljuk, így ü,84 g (70 %) Ifik. példa szerinti Ns(5fot6m-2-'piriáini:l)-2’{4-(ltidroxlantldlno)fonito4xmtlammej-5d)norfenükarböx~ < !(,>' fo p j s fo t <k i' < '- 5 t , ,bu s t it ufil í »» t <- v b ío tuti 9/t V» < « udk ο} u s η t tartalmazó víz/acetonttril eleggyel eluáíva fiszfousk, így 0,20 g (7 I %t terméket kapunk, MS C^HsjBrFNjQs (MAH)ő 472, 474.1.12 z (2.56 mmol, 1 x 6 equivalents) N A5 -bron - 2-pb-dimethyl) -N- (4-cyano-4-ylcarbonyl) -5,5-fluorenylcarboxylic acid, 0.2.13 gt 1.2 eq) HIDROS ANSI bldstsklöfid, the first push-EI ietli amm and 15 ml of ethanol was stirred overnight 5b 1 n C. The volatile components are then dusted off and the residue is left in its cells. Thus, 84 g (70%) of youth. Example Ns (5fot6m-2-pyririne: 1) -2 '{4- (lithydroxlanthldlno) phono-4xmtlammej-5d) norphenecarboxyl-3 (,>' fo pjs fo t <ki '<' - 5t, bu st It was refluxed eluting with water / acetonitrile containing 9 / v V / v of water / acetonitrile to give 0.20 g (7 L% of product, MS C 24 H 35 BrFN 3 O 4). MAH) 472, 474.
0,56 g (1,10 mmol. 1.0 ekvivalensét N-t'5-bróm-2--piridmll)-2-{4--(h«lrösiam5dino)fentlkarboriilart»«oj-5-Suoríemikarbö satuid. 0.50 g (5,0 skvlVáleos) cinkpőr és Ifi ml éoetsav elegyét szobahótnérséklfoen 45 percig keverjük, Azután szilijük, és a áznrlefei feepárí?lp.sk, A soamdékot 1IPLC cljárásSid (Cld kuditop fázis) 0,5 % trifioorecetsavat tartalmazó víz/aeetooitril eleggyel eluálva tisztítjuk. Így 0,24 a (44 %i N-ió-briSin-S-piridiniíi·foxtü'.auídn'-ofoniíkarbetiilaniinoj'S-'tlöörfonÍl.kiii'boxiiUiíöot (l ifi, példa szerinti vegyületet) kapunk. MS Cjoldí -Bit NA' fol l·» -''u fok.0.56 g (1.10 mmol, 1.0 equivalents of N-t'5-bromo-2-pyridyl) -2- {4- (hydroxyamino) -phenylcarbamoyl] -5-fluoro-carboxylate. A mixture of zinc dust (0.50 g, 5.0 g / l) and Ifi ml of acetic acid was stirred at room temperature for 45 minutes, then siliconized and the mixture was washed with 1IPLC of ClSide (Cld Kuditop phase) with 0.5% trifluoroacetic acid. purified by elution. This gives 0.24a (44% of N-io-bis-bins-S-pyridinyl) -fluoro-adiphenylcarbetylanoyl] -S-, chlorophenyl] -carbonyl (Example 1). l · »- '' u degrees.
HL PéldaOJ Example
A B ItrOa» puntnsdi 3 |4 (I untd onsdu/Bm í d3b ndk-u bordámon» 9 tbnn fonókat busám©A B ItrOa »puntnsdi 3 | 4 (I untd onsdu / Bm í d3b ndk-u ribbon» 9 tbnn spinner busam ©
1, Lépés1st step
I 6 < i, ' i a uh \ < s 'n.d' ' 0' d< '{ * ' L -,!í (>'!<< k< i fo'ii 5 dl nfc S U'folik* a'rtd 'fc ml ísiefoneUgl késKáit oldatába 0 aC'<nt telítésig kidrogéti’Morid gézt buborékolta-tonk, Az «legyet az«l>abömémWelea l éjszakán át keverjük, majd feepároljek. A visszamaradó anyag -egyötödéi: ÖJO g (2-aminoetd>medl· -•münoai 10 ml metanolban 1 éjszakái! át szobahőmérsékletei* reagáltatjok. Ezután az. oldószert csökkenteti nyomásost oltávolítjok, és a nyers termékei BPkC eljárássá; (OS.fordított fázis) 0,5 H trifltfofoéétmvát tártál· saszó víz/scetrmürd eleggye! otuálva tisztítják, így 0,082 g (37%) N-(S-bröni-2-piridií5Íl)“2-Íd-(knietil”2dmidazöitt5''3'djSí)SílkaÍ'b<snifeodsoj-'á't;!.törS5«dkazböxamÍdot kapnök, MS C$:dí;ssBrFNsOj (M-sfijkbOd, 49b, in-173,PékfoI 6 <i, 'ia uh \ <s'nd''0' d <'{*' L -,! Í (>'!<< k <i fo'ii 5 dl nfc S U'folik * a' rtd 'fc ml of isiefoneUgl knife was bubbled with 0 g of C'<nt saturated hydrogel gas, saturated with 'flour' overnight and evaporated to remove residual residues: 100 g (2-amino) > medl · - • muN in 10 mL methanol overnight at room temperature *, then remove the solvent under reduced pressure and the crude product was subjected to the BPkC process (OS Reverse Phase) 0.5 H triflofluoroethane · saline / mL The residue was purified by evaporation to give 0.082 g (37%) of N- (S-brown-2-pyridyl) -2-di- (nitryl) 2-diamidazolyl-5'-3'-di- S1-dicarboxylate. master5 «dkazböxamÍdot captain, MS C $: award; ssBrFNsOj (M-sfijkbOd, 49b, in-173, Baker
Λ kercmem uevlktekei a 1 i t pckiabar. leírt oiodvn aihttuk cinΛ kercmem uevlktekei a 1 i t pckiabar. described oiodvn cooled cin
5t«,5ti5t, '5ti
MX PéldaMX Example
MSíW-Hh s;.m, 54 í ) 13, Példa dl PéldaMSIW-Hh s; m, 54 () 13, Example d1 Example
MSfMeHk 526,538 'MSfMeHk 526,538 '
115. PéldaExample 115
MS{M*K):MS {M + K):
Séd.Sed.
MSfMiHY MgíMíH):MSfMiHY MgMiH):
Fit), .4.42 482,484 480,482Fit), .4.42,482,484,480,482
16, Példa16, Example
Γ??, Példa ld. PéldaΓ ??, Example see. Example
10, :Példa10,: Example
..••'te!..••'you!
ΑΧί ,,,,Ί ,,
I » .1 · teteteteAy'te:*''!;I ».1 · teteteteAy'te: * '' !;
XX,..,XX ..
MO (5Wl: 452, 4S4 . X-teMO (5Wl: 452, 4S4. X-te
MM sv-V'te íX.-X txMM sv-V'te íX.-X tx
M.W8);M.W8);
413.414413 414
OU *s ^g'OU * s ^ g '
ΓΓ
..-'5, .,. \..- '5,.,. \
120. PéldaExample 120
121. Példa un te'fo 'Xte te \.A^ r nfc.^ •te. 2 .2 Ay-'x-sS··' fo!Example 121. un te'fo 'Xte te \ .A ^ r nfc. ^ • te. 2 .2 Ay- ' x -sS ··' fo!
te is :you too :
5 tete.A tev...·· v<>'· *y te··''tes 5 tete.A tev ... ·· v <>'· * y te ··''tes
MS íbBHr 4éé, 4£>8MS 1bBHr 4y, 4 £> 8
Y *- >*γχ ÖyA^te’ te.í'te»··;Y * -> * γχ ÖyA ^ te 'te.í'te »··;
MS 04*H>; 440, telMS 04 * H>; 440, tel
124. PéldaExample 124
125. Példa yA,JExample 125 yA, J
Χ·-Χ· Χ -Χ
M,:i .MOfoPH); 452,4teM,: i .MOfoPH); 452,4te
122. Példa.Example 122.
ΧΧ'ΧΧ Λ 4 !i ’ΧΧ'ΧΧ Λ 4 ! I '
T ' w y*t te sX<;4> teteteT 'wy * t te sX <; 4> roof
..AJ..AJ
T (T te m, ...·>, *K; X <-At> T { T te m, ... ·>, * K; X <-A t>
MS (M+Ji);MS (M + H +);
412,414412.414
123. Példa ,-Ate X IX» tete, >ν·>·' •'•φExample 123, -Ate X IX »,> ν ·> · '•' • φ
MS íMfoH): 482( 4<teMS (MH +): 482 ( 4 <te
126. Pökhí126. Pokhi
AyAy
ÍJBOW
MS CMteHl: 480,482MS CMteH1: 480.482
127, Példa127, Example
- f X /W '<- f X / W '<
XZ £ >«L yXZ £> «L y
Xy'Xstf'Xy'Xstf '
-η, teXte-η, teXte
M$ fM'í'H). 4g§t 500 au íySjte <,..··' XAfo»M $ fM'í'H). 4g§ t 500 au íySjte <, .. ·· 'XAfo »
I nj ..-^, te; í teyAX né,I nj ..- ^, te; oh teyAX,
U teU you
Χ;χ; Χ ; χ ;
MS (Mfolp 405,492 fo<MS (Mfolp 405,492 fo <
fov- yx tegPsteJ a ny,.··fov- yx tegPsteJ a ny,. ··
X y'XX y'X
XX
MS í'MíHl 430. 432MS 1 H-NMR 430. 432
V'te, te J<s, ..45 Ύ y sy-XíApV'te, te J <s, ..45 Ύ y sy-XíAp
MS (M3H): 45S. 464MS (M 3 H): 45S. 464
128. PéldaExample 128
129. PéldaExample 129
XO. PéldaXO. Example
131. PéldaExample 131
Γ ρ'VJΓ ρ'VJ
..''Χ··'^ f-'>·' yx r on * t AX.« xx-'! W xM mm·.. '' Χ ·· '^ f -'> · 'yx r on * t AX. «Xx-' ! W xM mm ·
X.-’' 'Y'teyte ?· >*te ^yxX.- '' 'Y'teyte? ·> * Te ^ yx
-Atete. xX-jte gy-te-.-Atete. xX-jte gy-te-.
W*S ,.?·<W * S,.? · <
u,„ y 'su, y's
Ü ΊÜ Ί
Χγ · ·><>Χγ · ·> <>
£Kx..'Xte'te$; £ Kx .. 'Xte'te $;
Xyxy
Ute,Ute,
Γ r rΓ r r
Pyteste·'· Pyteste '
Χ·χ é AΧ · χ é A
X <y \ teX-s teS if\ a t aX <y \ teX- s teS if \ ata
MSlMWp SÍ 3,513 .Mdfo-PHO 54,8, 550MSlMWp SiI 3.513 .Mdfo-PHO 54.8, 550
MS IM HI'S. 530, 532MS IM HI'S. 530, 532
132, Példa132, Example
1.13, Példa1.13, Example
134. PéldaExample 134
133. PéldaExample 133
öi-i aM''M '7 v-2öi-i aM''M '7 v-2
Ϊ5 Ϊ 8 -< x>- x,Ϊ5 Ϊ 8 - <x> - x ,
MS (MM!): 4,26, 425 <yX.«y,MS (MM +): 4.26, 425 <yX.
ΎΎ
MSIMUM 428, 439 i Ί „ vS <· -¾^ χΜ xo >:S*Y.MSIMUM 428, 439 i Ί „vS <· -¾ ^ χΜ xo>: S * Y.
MSlM'Kl. 424, 428MSlM'Kl. 424, 428
MS (M+H)· 428,439MS (M + H) - 428,439
136, Példa ?, Példa136, Example ?, Example
138, Példa138, Example
139, Példa.139, Example.
•07 .vJ ,<-;• 07 .vJ, <-;
y y:<s yy : <s
-X ) 4 Mx-·'· A-·X-M X,,.-X) 4 Mx- · '· A- · X-M X ,,.
MS {M+Hp 452. 4S4MS {M + Hp 452.4S4
F , ο n,F, ο n,
Y r $ .ν·χ.Y r $. ν · χ.
F , cnOF, cnO
146, Példa r146, Example r
öΌ -a ν As-'AMJ * ίΆ.,.,-χ.öΌ -a ν As-'AM J * ίΆ.,., - χ.
-X .4-X .4
X;^'* xpX; ^ '* xp
V4 is ;iV4 is; i
SfSf
Ys>AYs> A
528, 530528, 530
144, példa xY'Oy'A *OMExample 144 xY'Oy'A * OM
0AÁy «ΝχΜχ0AÁy «ΝχΜχ
La '8,La '8,
MS {MM1P 474,476MS {MM1P 474,476
MS.. Példa > ΊMS .. Example> Ί
SyYA,SyYA,
X. -i-ix .X. -i-ix.
MS CMW 470,472MS CMW 470,472
141. Példa .χ·· Χ .. χ.'Ά ú-‘Sx r 9 6 η a.4 AyAy *Example 141 .χ ·· Χ .. χ.'Ά ú-'Sx r 9 6 η a.4 AyAy *
χογ sY-yχογ s Yy
ΛΑ .χ’ζ.Άν —' >ίΛΑ .χ'ζ.Άν - '> ί
MS sM-n if: 5ίΌ, 56?MS sM-n if: 5ίΌ, 56?
145. PéldaExample 145
ATHE
ΆχΥΆχΥ
Xp^xM-* rXp ^ xM- * r
4X44X4
ΎΎ
ViVi
MS (MAI): 450,442MS (MAI): 450.442
149, Példa149, Example
ΧΪΖ'ΛχγΖίΧΪΖ'ΛχγΖί
99,.,.-¾..99,., .- .. ¾
AyAz-y s^\.Ax.AyAz-y s ^ \. Ax.
oySí'Y *?'>..·- -·. .:Ή·oySí'Y *? '> .. · - - ·. .: Ή ·
-•x.-- A::-:‘A,-:4>- • x .-- A :: - : 'A, -: 4>
(SW 482.454 '4.' Pcida{SW 482.454 '4.' Pcida
Μ^,,-'Χ-ύ-Χχρ “ΛΜ ^ ,, - 'Χ-ύ-Χχρ' Λ
MS£MWMS MH + £
496,606496.606
1A P-x 3 ουΌύ íYYX 9χ.,4 yMxys L„4 Χα ’* Αρ I ,χΐ -ρ íY<.Ax,;S>\·1A P-x 3 ουΌύ íYYX 9χ., 4 yMxys L „4 Χα '* Αρ I, χΐ -ρ íY <.Ax,; S> \ ·
Υ Χ '4Υ Χ '4
Ύ χ-· 'SíΎ χ - · 'Sí
MS íM-rtl):MSM-rtl):
544, 546544, 546
146, Példa146, Example
99,,99 ,,
MS<MMi)· 543, 544MS <MMi) · 543, 544
147. PéldaExample 147
0iS! 0iS !
N$-AN $ -A
o.She.
χ·'·χ·Α í «6 ''<γΛΧί=:· χΜ,χ,6 · '· χ · Α í «6''<γ Λ Χί = : · χΜ, χ,
OSHE
X-' Xg,X- 'Xg,
MS <M s-H>; 456,458 rTX,/MS <M sH>; 456.458 r TX /
Yá.'-SívYa .'- SIV
T ier-yyT ier-yy
AAy<>AAY <>
ί :ΥΆ...··Ύχ •v 1 7 γ-γί: ΥΆ ... ·· Ύχ • v 1 7 γ-γ
O'YO'Y
MS£MM1). -47<\ -4 /·4MS £ MM1). -47 <\ -4 / · 4
151, Példa151, Example
156, Példa156, Example
448, W448, W
152 Példa152 Example
IX π n .., c;s\ --'í v·’IX π n .., c; s \ - 'í v ·'
M **Ά%M ** Ά%
Χγ-'·· teA-j, rfo, ....¥ uΧγ- '·· teA-j, rfo, .... ¥ u
Μ.$(Μ-ιΉ>; 476. 472 teΜ. $ {Μ-ιΉ>; 476. 472 te
157. PéldaExample 157
158, Péloa158, Péloa
MS (Mf-H); 514,518MS (M-H) -; 514.518
155, Példa «Η155, Example «Η
Λ .iAi ¥ te k ..A ,aΛ .iAi ¥ te k ..A, a
XnXn
Ά^lí ^sA *'·' xSfΆ ^ lí ^ sA * '·' x Sf
MS (MW 408,498MS (MW 408.498)
156. PéldaExample 156
156. Példa w χ ..-A ,-o T 5 terAA:Example 156 w χ ..- A, -o T 5 te r AA:
MA \XCi MA \ X Ci
MS íM-i-UrMS M-i-Ur
484, 486484, 486
M MM M
s.P γ·<s.P γ · <
ΧΑ-Μ !<<X te’ tefíi ΧΑ-Μ ! << X te 'te fíi
MS(Mí-Hí: 488, 5(X) >te<i í kMS (M + H +: 488, 5 (X)> te <i> k)
V'VA ΓΤΛ ! MA5 xj I» A ;.o /' ί*%.·-κ, p A-te,V'VA ΓΤΛ ! MA 5 xj I »A ; .o / 'ί *%. · -κ, p A-te,
- í 1 &M·- í 1 & M ·
100. PéldaExample 100
1.61. Példa \··'1.61. Example \ ·· '
IX.IX.
ΌΌ
MSfoW}· 470.472MSfoW} · 470,472
182. PéldaExample 182
JAJA
X'X v-} MaX'X v- } Ma
Xy-fo;::··' A 4i li JXy-fo; :: ·· 'A 4i li J
MSiM-i-Hr SKi, 512MSiM-1 Hr SKi, 512
F x'vSrmF x'vSrm
M: ma * MxM : ma * Mx
A'UA'U
A-Xx 'te AA-Xx 'you A
MSíM-t-H): 542, §44MS (M-t-H): 542, §44
V#*·?· V * #?
Y’^Y a =
\.x am»\ .x am »
164. PéldaExample 164
165. PéldaExample 165
AX «%.AX «%.
LAciLaCie
MSíMÜl), 500,502MS (M + 1), 500,502
163:, Példa163 :, Example
ΜΆΜΆ
HKXy-Ai··HKXy Ai ··
A-X teA-X you
MS (M-i-Hl: §26, 528 ^-tegr MS (Mi-Hl: §26, 528 ^ r -teg
MS (Mi-H): 52.4, §26MS (Mi-H): 52.4, §26
168. PéldaExample 168
187, Példa tg (I187, Example tg (I
$?$?
,.·Χ\ ige' y χ,. · Χ \ ige 'y χ
S· Ορ ...-¾.S · Ορ ...- ¾.
ZttA,,.ZttA ,,.
tx \Ζ!tx \ Ζ!
MS (MOU:MS (MOU:
444-,, 449444- ,, 449
HU.EN.
^XaXa ^
MS <M WMS <M W
446. 445 i?2. Példa446. 445 i? 2. Example
m. Példa .1, Elödhitási példam. Example .1, Predictability Example
Μ-(2~| A-rk-PromM-pb ulttáus tárnod! kS-'dtuoousdeudlpt'emeot'eud'SkuthoviHnldΜ- (2 ~ | A-rk-PromM-pb Ultimate Storage! KS-'dtuoousdeudlpt'emeot'eud'SkuthoviHnld
x.x.
N<N <
HH
7' < y7 '<y
2,2 g (tö mmöl}4,5x1 mtétökiÁ-tslíróbettzöésáv és 2,4 « (14 insnttl) 2-aetlstö'-54>íomgiridtö 59 ml viza srtestes pitiöhtuei készük okiamhoz Ő C-ött 1,9 sói (29 mosol) IbsmbZ'OSS'kltsrsdei admsk, Az: elegyes szobitöm nsersókletes:t 29 perelg keverjük, ezalatt s reakció tekeson végbemegy. A retskaióslegyet bepártdmk, és a mttríe dákot 209 od eíö-acstármi higítjal·. Á szerves oldatot Selltet· vizes nátrium-kloríd-oldattal mossuk, szárítjuk és begácotjuk,. Így 2,9 g (89 %) f, szárott ktiztmttóá yegyüküet kgpátÍk, Mb CMlaelárAbCb (Mt ii) : 382,99, 383,95,2.2 g (moles} 4.5 x 1 of methacrylate librobutane strip and 2.4 g of (14 insnttl) 2-acetyl-5,4 g / g of gyridide were prepared in 59 ml of water-borne phthalate with 1.9 C salt of 29 (29 moles). IbsmbZ'OSS'kltsrsdei admsk, A: Mixed room volume is mixed with salt for 29 hours while the reaction mixture is quenched and the filtrate is diluted with 209 volumes of dilute aqueous solution of organic solution. solution, dried and stained to give 2.9 g (89%) of the dried product in kgpat, Mb CMelarAbCb (Mt ii): 382.99, 383.95,
2.20 ou; (0,83 romol) I. sz közbonsü vegyiket, 990 mg (4,9 romol) öo(ll.s--klobd-dihldrát és Hl rőt etil-tteesát élegyél 1 órán át visszalólyótás kőiben törtaljok. űzőink a redekeiö teljeseo lejátszódik, A szilárd anyag Celke ágyon, át kiszűrtük., A szürleíeí 59 ed etli-geátéltni higbjak, ás a vörös oldstot károm aik.&loounal löt vizét;2.20 ou; (0.83 romol) Intermediate I chemicals, 990 mg (4.9 romol) of oo (II.s - clobddihydrate and HI) ethylteteesate live for 1 hour in reflux rocks. The solids were filtered through a bed of Celke. The filtrate was diluted with ethylene and water was added to the red liquid.
nátríum^hidroxid“O.lda.tíal, ntgjd telített vizes'náírmm-klorld-oidaltal mossuk, szárítjuk és bepámljnlg így 23ü nsg (78 (> é ? \z<'U ,. kt\‘\ ' ,<g ? , et \ ivó 5\ \ k Ci dl Ut‘ b bx -s? Ot -m- usodium hydroxide was washed with O.l.t.tal, ntgjd saturated aqueous sodium chloride solution, dried and evaporated to give 23 .mu.g (78 ( >), < g > et \ ivó 5 \ \ k Ci dl Ut 'bb x -s? ot -m- u
2öö mg (0,57 mmol) 3. számú közbenső vegyület 3 tel piriöinnel és 10 sül diklöftnétáPPál készük «kínoshoz. 140 mg (0,85 mmol) 4-claaobeRzetl-kioridot adunk. Azosmal csapadék képződik és a reakció teljesen lejátszódik. A szilárd anyagot szűréssel összegyditjök ős dikiótnsetánmd messek. Vákaumbaa végzett szárítás márna 11 n ut Ί) s, 's s '.'e·. Ό 'P v't ' -·,'!!.< sz < ni i«' »> ibks ,1' m u 'p í, M’ t \ Bit·’ tg K\i b' 481,00,483,09,Intermediate 3 (2 mg, 0.57 mmol) was prepared with 3 portions of pyrroline and 10 dichloromethane. 4-ClaaobeRzetl chloride (140 mg, 0.85 mmol) was added. Azosmal precipitates and the reaction is complete. The solids were collected by filtration from ancient dichloromethane. Vákaumbaa drying dried mullet 11 n ut Ί) s, 'ss'.'e ·. Ό 'P v ' t '- ·,' !!. <Sz <ni i «'»> ibks, 1' mu 'p í, M' t \ Bit · 'tg K \ ib' 481,00,483,09,
174, Példa {4x5»lííKíeU'\! 3-14a 1 -nsctd 7dmsda/<4kiC-dUe«dSmshn«damtnojlea$í| 'V(?-brm«'2-pariddt kaíhnxandd174, Example {4 x 5 »lilKeU '! 3-14a 1 -nsctd 7dmsda / <4kiC-dUe «dSmshn« damtnojlea $ í | 'V {? - brm «' 2-pariddt kaíhnxandd
100 mg· (0,20 mmol) 1. elöáldiásl példában előálitlöit vegyidet 10 : ml 10 %-os .píridiaes íristii-simm-ekladííl készük oldatába 0 í:C-oo lelkesig szidsz Iddmgén-szsribd gázt huhorékoitanmk. Az begyet környezeti Stöntőrsékleten 1 éjszakán át keverjük, ezaiatí az átalakulás teljesen végbemegy. Ezután uz eíegyet szárazra pároljak» a maradékot 10 ml vízmentes acetonba» szaszpcndaljak, é.s a szuszpenzlöhoz 1 ml metsi-jodkmi adónk, A reákeióélegyet | órán ál visszakéystás közben rbtraijak. inad az oldószert íörgdkészdlékixm lepátölj'uk. A maradékhoz 10 ml vízmentes metanolt é.s 1 mi 'N-meltlctiióndiamtnt adunk, Á képződök eíegyet 1 áfás át visszáfolyatás közben fortaljak, majd bepároljuk és RP-HPLC eljárással tisztítjuk'., így a· cint szerinti vegyületet kapjuk, MS CWl-uörNsCki (M-*Hf; 55S.I. 540.1.· 100 mg (0.20 mmol) of Example 1. elöáldiásl előálitlöit vegyidet 10 ml of 10% .píridiaes íristii-SIMMs ekladííl finished solution t 0: C oo LELKES szidsz Iddmgén-szsribd huhorékoitanmk gas. The batch was stirred at ambient temperature for 1 night, at which time the conversion was complete. Then evaporate the mixture to dryness »dry the residue into 10 ml of anhydrous acetone» and add 1 ml of methyl iodine per slurry to the slurry. an hour-long breeze rbtraijak. inadvertently remove the solvent. To the residue was added 10 ml of anhydrous methanol and 1 ml of 'N-melted-thiamine diamine', the resulting mixture was refluxed for 1 h, then evaporated and purified by RP-HPLC to give the title compound, MS CWI-1. (M- * Hf; 55S.I. 540.1.
175, Példa175, Example
4-(N<42-jN-(,5-SÍróni2-p5ridii)kaí’bttn!ödj-4,5din!efmsilén.il|.kar.bassödjfenslkarboxastldin! 4- (N <42 jn - (5-SÍróni2-p5ridii) kaí'bttn ödj-4,5din efmsilén.il | .kar.bassödjfenslkarboxastldin
A um i’ennd vegyületet az I, elöáküásipőida szerinl t vegyüietböl áilkink ele. MS CndboBt'N.T).; tlvbHV 4OgJ, Akkő,The compound of formula I was prepared from the compound of formula I, precoated. MS CndboBt'N.T); tlvbHV 4OgJ, Stone,
SS, ESöidiaúb példaSS, ESEidia more example
N-íS-Klör-í-pjrídOrfS'-jfd-enmoScttölkarboniiaminoj-^mctoxSfaaiSkafboxgntidN-IS-chloro-t-pjrídOrfS' JFD-enmoScttölkarboniiaminoj- ^ mctoxSfaaiSkafboxgntid
''a? - ·.íüí’í \ ό,υο rtc: ' tuiext 1 'üíseb,s\'\< ovo' e\ ' sooso s k'O'pnukfg,» «listád· clb?/ t ek< álitwr-ekUw Seat dge oMs \is t ti t'v>v\i tv- O'd no, Fékó''the? - · .íüí'í \ ό, υο rtc: 'tuiext 1 ' siiib, s \ '\ <ovo' e \ 'sooso s k'O'pnukfg, »« your list · clb? / T ek <alitwr-ekUw Seat dge o M s \ is t ti t'v> v \ i tv- O'd no, Brake
N-éF-Kksr-l-pirstbO-ő-í'sseifíXí'-l'gid-Cbfííatb-S-sniiibrzisUíS'-á-ildeíSígksíS'bsrííihífísisssrHcndkai-boxasnsdN Kksr EF-l-o-pirstbO í'sseifíXí'-l'gid-Cbfííatb sniiibrzisUíS'-S-a-ildeíSígksíS'bsrííihífísisssrHcndkai-boxasnsd
L ,b\L, b \
N, aSo
1ÖÖ Ság l.k elösbsiásí péhó szériád vegyidet § Ml VíZshesdes snetastolól és § ml eíd-aeetsöss készük szttszpenzójába 0 'C~ott telítésig vízmentes hidrogéo-kis>riii gázt buboréksritalunk, Az elegyet környezeti hőmérsékleten 1 éjszakást. át keverjük. Ezalatt: mt átalakulás teljesen, végbemegy, Ezután sz Negyei szárazzá pároljuk, a maradékot· It) tol'vízmentes metanolban oldják, és ez nklatboz 1 rsd N-s«eísÍetiiédiaaris« adunk; Á képződött elegyet 1 órán át visszafötysstás közbéó IbrZidpik, majd bégároiiuk, és: a ásarádékoi, BF-Íj:PÍ,C eliátássól t '-rtu? k tnUíikb ousze<<ί i u Ί > í\ o Ml· dl100 ml of water were prepared from a mixture of § Ml of water shesastol and § ml of water-aeetsöss to 0 ° C until saturation with anhydrous hydrogen small gas bubbled overnight at ambient temperature. stir. During this time: mt conversion is complete, then the mixture is evaporated to dryness, the residue is dissolved in toluene-anhydrous methanol and this is added to a solution of 1 rd of N in ethyl acetate; The resulting mixture was refluxed for 1 hour with IbrZidpik and then beagle, and: from Asaradekoi, BF-Bow: PI, C elution t '-rtu? k tnUíikb ousze << ί i u Ί> í \ o Ml · dl
177, Péisó177, Péisó
W<'N-{2-jsX-(5-K.téi'-Ö-ptrídlljkarb8Ínödk-4-'áietovlléíidjkArbamoiijíést0kávixsxstínkbttW < 'jsX- N- {2- (5-O-K.téi' ptrídlljkarb8Ínödk-4-'áietovlléíidjkArbamoiijíést0kávixsxstínkbtt
OMuOmu
k >.í í szus <it se»'é sá << E ·.let s tv vE V>> t ι í k\>s t ' ntkl· - t s uo d . su <d b'htj κ elő. MSC-di^C-NgEtM^l· :?tk> .i sus <it se »'and s << E · .let s tv vE V >> t ι í k \> s t' ntkl · - t s uo d. su <d b'htj κ pre. MSC-di ^ C-NgEtM ^ l ·:? T
175, Féids175, Féids
V(5-Klof-d-psridü)-2-(4'iuntn«dtnettlííni{nnt«}eld|teodkarb«>nttsmtinol-5 mvJ<’\tfe«»lkarbo\a»nitJ ^<•5:V (5-Clofd-d-psridyl) -2- (4'iuntn «dtnethylline {nnt«} eldododcarb «> nttsmtinol-5 mvJ <'\ tfe« »lcarbo \ a» nitJ ^ <• 5:
A'· ,--¼ x χχ.-· V ,,AA '·, - ¼ x χχ.- · V ,, A
X ».·$α.X ». · $ Α.
•\·:·'·* \»·Αξ• \ ·: · '· * \ »· Αξ
A cd» szerinti yégyilbípí .a bí'4S-k:lör-2-psrsdll)-2-(4-ebs)óleadki4d9i)dan)íab)'-S-IPSb>s)1es)biarbos: a' K ' xx ' et x' nv > * \ ' >x \< m ; J Jxx' Yt\ h - ..?' Μ i ' i'sThe cd »bis-4-s: l-2-psrsdll) -2- (4-ebs) lead (d) b) d) b) - S-IPSb> s) 1) b) : a 'K' xx 'et x'nv> * \ '> x \ <m; J Jxx 'Yt \ h - ..?' Μ i ’i’s
17A Hdda (7-(4-|{(>Hí5<'ítlam{R»J)»}Ü!an8Retí?lfeí54kat'bí«i5la{nj?!o}S'«j<h}Mfet5Ő)-'N'(5' Mór- 2-pií'íööskarbrtxansjd17A Hdda (7- (4- | {(> Hí5 <'judgment {R »J)»} Ü! An8Retí? Lfeí54kat'bí «i5la {nj?! O} S'« j <h} Mfet5Ő) - 'N '(5' Mór-2-piilosylcarboxyl)
MHMH
X.. X (1 X uX .. X {1 X u
.. V \ .A-A X 1 8 ki' \ %, ,.ŐH Ö v, .-vr o.. V \ .A-A X 1 8 ki '\%,, .ÕH Ö v,.-Vr o
SASA
A dm szerbi) vsgybbtet a ^-OMór-S^MóHj-S-C^das^tibnük&rbódlmnidó^m^óXlíMH· (χχ \ i! ! ! x x!! X ! ! 5 > S ' ' 1 x' 1( \ ' θ x Λ V\ > B \ x » .V -SDm Serb) vsgybbtet the ^ -OMór-S ^ MóHj-SC ^ das ^ tibnük & rbódlmnidó ^ m ^ óXlíMH · (χχ \ i!!! Xx! X! 5> S '1 x' 1 (\ "θ x Λ V \> B \ x ».V -S
S8V« PéldaS8V «Example
V<5-Rkrt'EpÍrídH'2' (ΉIfstmaspirs'fdkhssdpssvSitlfessdkarbaísdaramssj 5 ísadassleisdkasbavstisdd í'.ASs iV <5-Rkrt'EpÍrídH'2 '(ΉIfstmaspirs'fdkhssdpssvSitlfessdkarbaísdaramssj 5 ísadassleisdkasbavstisdd í'.ASs i
.A .g..A .g.
.·. ·$’<*” v\. íJ A3 *»·' \·>·*·'’\χ ..''’λχ ti ¥ Ί x':$5' kíH .,.,-x X W { kt' Τ X ...NH ο K W W Ύ ^· · V. ·. · $ '<* ” V \. íJ A3 * »· '\ ·> · * ·''\ χ ..''' λχ ti ¥ Ί x ': $ 5 ' kíH.,., - x XW {kt 'Τ X ... NH ο KWW Ύ ^ · · V
Vi i < friüw,'sd. s í 1 > ' í'!i Os? x-> x xjsxbss kaslass A<st\5 sedovte'eskashx.sushltv» és pmÁkÁböi ádilhlk elő á 1 7b pbdábái sesb eljárássak Mis tdjJACÁsCb (Méíkf: 478.Vi i <friüw, 'sd. s í 1>'í'! i Os? x-> x xjsxbss kaslass The <st \ 5 sedovte'eskashx.sushltv »and pmÁkÁböi adilhlk pre á 1 7b pbdábes sesb procedural Mis tdjJACÁsCb (Míkf: 478.
Í8L PéldaÍ8L Example
AMMKbs'-2-plr(dit}'2'44''Híbnts(pipebdihsaeldjRfbbart5<mösk«di>»j-5-mb!>bléaökarbewnidAMMKbs'-2-PLR (dit} '2'44''Híbnts (pipebdihsaeldjRfbbart5 <Moskal «di>» j-5 mb> bléaökarbewnid
OMaOMA
X mX m
I ah χχχ& ·$<I ah χχχ & · $ <
X* \s-· <X\x. ,·'Λ>Χ.X * \ s- · <X \ x. , · 'Λ> Χ.
! il xW'X 0 ,s=m ί! XX \í'z 0! il x W'X 0, s = m ί! XX = 0
A elm szesbdí vegyidelei N-ls-klorM-piridi 1)-2-(4-•eimmfenökmhönömnbe) A-melox dWtehöSxWtidM és pisblbbb aililbsk elő a 174, példában le ;r; eibbssb. Ma Cr,f:.HsXIN\O? |M · HM 492,The chemical compounds of N-ls-chloro-M-pyridine 1) -2- (4-dimethylbenzene) A-melox dWtehöSxWtidM and pisblbbb allylbsk were prepared in Example 174; eibbssb. Ma Cr, f : .H s XIN \ O? | M · HM 492,
4á fefe, Példa ri-<S-Kiőí--2-p5rídd}-2-{44 imsn»(ss«rfeksí'4-4Űínetdji«s5.dbarbímÍÍsriúirin}--SUsefexsfesiikísrbóx.uarid4afefe, Example ri- <S-Kiil - 2-pyrid} -2- {44 imsn »(ss« rfexi'4-4 «din« s5dbarbimirriurin} - SUsefexsfesikisrbóx.uarid
Λ eim szerinti vegyüleset N•iS-iíióíCkpifiddl-y.-íd-e'.anotendkía'bonilíansnoi-á-ífieíosifeiriikarboxau-xIbói és ruofiöbnböl áíihjak «fe s 1 ?b. páidábsk leírt eljáíásssk MS CM®fedNsö.! íMfel)’: 494, LThe compound according to the present invention is a mixture of N, 5'S-lyolylcypifidyl-yd-e'-anotendkylbonynylansnool-aliphosphorylcarboxylic acid and rhodium chloride. Refer to the procedure described for MS CM®fedN s . mph): 494, L
183. Pékla183. Baker
MriS-KMs-S.-psrkídl-l-'kí'-lííJtsnO'-i k4''dsízaperbidyo5n-4-sí)mefil|fe5JÍyiíH'boiiSfembtpi'S'3détoxG fenilkarhosanridMriS-KMs-S.-psrkdl-1-'kí'-l'InsnO'-k4''disperaperbidyo-5n-4-syl) mephrine fe5JiyiiH'boiiSfembtpi'S'3détoxG phenylcarbosanide
$ no$ no
A eim szerinti vegyületet N-<Skt6f2-pRi<hi)-2<4»eianofe«iikarb<mifetniru>p$-n)«toxifettkartx»«tniKlbót és tiemoriblinbbl állítjuk elő a 176. példában leírt eljárással. MS C2SH2<C1N$OjS (MvR): 51Ö.The compound of the present invention is prepared from N- (Skt6f2-pRi (hi) -2 (4) cyanophenylcarb <mifetniru> (p) -n) "toxifetcartx" tinCl 2 and thiouribline according to the procedure described in Example 176. MS C 2 S H 2 < C 11 N 8 O 5 S (MvR): 51 °.
144, ifekta (2-Í4·· j Ansisughidrosiarinirinséi iyfeniíkaríé.snikuírinid·S-níekíxsfrsid)·N (S-klór2-piririií;· fearboxanúd144, ifekta (2-4 4 ··· Ansisughidrosiarinirinsilylphenylcarboxylic acid) · N-hydroxy pyridyl · fearboxanide
Μ ..-¾ 12Μ ..- ¾ 12
Cí í 50 mg N'{5-k1í>y'-2'-pirsd5!}fe44-c;aÍSofeídÍkí4'boy!dí!m;«ó}fe-A;«tóxiiendkafeoxásnfe Μ Ari okmofed készült szuszpenzldjához 88 mg bidrexil-mnövhiárokiorídel és 200 pl trieíd-amint: .adunk: Az «legyet bö ;>€-oo I éjszakán át keverik® ezafeb: a reakció teljéséit végbemegy. Az oldószert lepáririjök, és a nyers· attyagöí fek“HPLC ubarsssal risztítjvk, így a dm szerihri Végyáletet kapja® MS C:gR:fe4N$Ck (MAR)': 44ÖU.To a suspension of 50 mg of N '{5-chloro-1'-2'-pyramid5-fe44-c;aisofeidic-4'boyl; o) fe-A; mnövhiárokiorídel 200 such as trie: .adunk: Bo "birds;> € -oo for overnight keverik® ezafeb I: the reaction is advanced teljéséit. The solvent was removed by evaporation and the crude solvent was subjected to HPLC ubars to give dm serihri Vaccine® MS C : gR: t4N $ Ck (MAR) ': 44.
Ri i'kkrifeáss példaRi example encryption example
N-{5-Brnnte2-pirjdli>2-(4“eiandf8»S|k«y|jp»iÍ8»)ian>S“8ieíoxlfe8lllínrb«san?idN- {5-Brnnte2 pirjdli> 2- (4 "eiandf8» S | k «y | jp» iÍ8 ») ian> S '? 8ieíoxlfe8lllínrb" san id
4.64.6
A moí sjcrnü! ségvtsb'tet Mnemxi-C'rujyKnztx. wbol es .MrminO'^brótnpindsnhöS aliánsk eiA ,?/ I előálbátí-1 példában leírt eljárással. MS C>:l-l5;.13f'NA).i (Μ·*·ΗΓ: 451,00. 453,00.Moi sjcrnü! ségvtsb'tet Mnemxi-C'rujyKnztx. wbol and .MrminO '^ brindle spindle subunit according to the procedure described in Example 1A. MS C>: 11 5 ; .13f'NA) .i (Μ · * · ΗΓ: 451.00. 453.00.
185. Páhbs185. Pahbs
N-{5'Oró5ís-2-psrfdsl}-58S'feínsl-314'{S'S!seSíi-2~siííSfibsz<slsn'2-ipterssikarbes8s'ls55Sihss>ll'efsllbnrb«sas«!d öbá>N- {5'Oró5ís-2-psrfdsl} -58S'feínsl-314 '{S'S! SeSíi-2 ~ siííSfibsz <slsn'2-ipterssikarbes8s'ls55Sihss> ll'efsllbnrb «sas«! D baba>
í 11
4. k/« i 8 u \ K ,nw o4. k / «i 8 u \ K, nw o
W'T óW'T oh
V'V '
Η !Η!
VfrVFR
510.510th
A cöa szérimí vegyiMsret a 170, pélásbals lézrt eljárással álllemk elő.. MS QylEAiW;; (Md'HY: SOSThe serum is chemically synthesized by the 170 laser cutting technique. MS QylEAiW ;; (Md'HY: SOS
18b. Példa18b. Example
24\-{2iN-í$Bí-MH~2'p5Fkhi)kstí b24 - {2iN-1 $ Bí-MH ~ 2'p5Fkhi) kstí b
ÖMsOMS
NHNH
Λ ✓ ? .4. 0Λ ✓? .4. 0
8V ,S. 8V , S.
i > γ χ =x,- $ oi> γ χ = x, - $ o
Ofof
Ά élni fiZeriatí vsgyüiéíét a 176. péiőábats leírt: eljárással állitjal;: elő, MS C^HísBzWM íMH-íf; 468,05Ά to live the phyryoid assembly as described in Example 176: by the method of producing: MS C ^ HísBzzWMMMH-ff; 468.05
470,00.470,00.
187, Ráláss187, Look
N-t5'-SrofS5'S-pirbbl)-l {djbnbsofsíst'tibsnssísnssssrSOllesisOiarbnííOaíasnní'S-BseSwvsfrftáksrs'bcvssníá nw il.N-t5'-SrofS5'S-pirbbl) -l {djbnbsofsíst'tibsnssísnssssrSOllesisOiarbnííOaíasnní'S-BseSwvsfrftáksrs'bcvssníá nw il.
..... YXAA A Ο L. J...... Y X AA A Ο LJ
X' ·*·γ •'V.rtS*'· rt 7fX '· * · γ •' V.rtS * '· rt 7f
A cím szerinti vegyületet a 176. példában leirt eljárásaid állítjuk elő. MS í.ődfojSrN/.)! (M-d-lJ: -182,The title compound was prepared according to the procedures of Example 176. MS.pdfojSrN /.)! (M-d-1J: -182,
454, tSS, Pébte (2'já'jO>üneNÍ8nsinis)bnnínt8etil|feníik£rbn«ítomh5ö|-'S'-5neÍosifesüE.N(5~büins~2''454, tSS, Pébte (2'já'jO> üneNÍ8nsinis) bnnínt8ethyl | phenyl £ rbn «judomh5ö | -'S'-5neíosifesüE.N (5 ~ bünins ~ 2 ''
-pl ndh) ka rboxís sn id-pl ndh) ka rboxís sn id
A étin szersííb végyületét a 176 példában léid eljárással állítják elé. MS CdstEáErNsÖ;; íM s Η}': 496.1.The edible end of the food is exemplified in Example 176 by the steeping process. MS CdstEaErNsÖ ;; íM s Η} ': 496.1.
499,1.499.1.
159, Példa159, Example
N'jS-Klór^-pirldiij-S-^á-pinisníphTtshdiuíOmetdifesiyksrboníiamsKöj-'S’meínsífosdion'bexanddN'jS-Chloro-S ^ a ^ -pirldiij-pinisníphTtshdiuíOmetdifesiyksrboníiamsKöj-'S'meínsífosdion'bexandd
N,N,
8r8r
A ebit szerinti vegytdéíet 3 176, péiAábs» léid: ídjárá.s.sal aiKíjüfc élő. MS &$Η;ί,<δΓΐ%0:ί (MziTy; 532,The ebit décolleté 3,176, péiAábs »leid: ídjárá.s.sal aiKíjüfc alive. MS & $ Η; ί, <δΓΐ% 0 : ί (MziTy; 532,
5.24.5.24.
199, Példa199, Example
M-(N~(SBr6m>2-ph'idí:l>’2{4'4dninöü8pés6dii}mel:djíe55Siksrbonlhm5innj'Smei:nxite8rlknrh<ssíNnidM- (N ~ (SBr6m> 2-ph'idí l> '{2} 4'4dninöü8pés6dii mel djíe55Siksrbonlhm5innj'Smei: nxite8rlknrh <ssíNnid
A. eira szettntí vegyületet a 176, példában léid eljárással álbijok elő, MS CW'i:isA'bbO:> (MMjj’: 546,1,Compound A. eira was prepared by the procedure of Example 176, MS CWi: isA'bbO:> (MMjj ': 546.1,
I9P PéldaI9P Example
6i*(S*8í’s5!»-2{drklíi)-2j4<jinf{tH«(5Mi>ribl5u-4“>l}metUífe!fülk8rhosils?nsnoj-5-jnetoaífenilkarbos:a«»d6 R * (! R * 8í's5 '- {2 drklíi) -2j4 <Jinfan tH { «(5Mi> ribl5u-4"> l} metUífe fülk8rhosils nsnoj-5-jnetoaífenilkarbos the «?» D
539,539,
\ ! S'U ί V 1\ ' Ϊ 1 η s\ dd<< } η η κχ\κ Μ V\k ?’ η \-A\tV Η4 \! S'U ί V 1 \ 'Ϊ 1 η s \ dd <<} η η κχ \ κ Μ V \ k?' η \ -A \ tV Η 4
54(11, (92, Példa .NriS-Brórá'á-íSíddiO-S-j^-lbrtleö-Cl^-őazaperhíd.folft'^-stíwetai'ffeBÖkarbonHsmleol-S»54 (11, (92, Example. NriS-Broma-α-Sidi-O-S-j) -1brtleol-Cl ^ -azazaperhyd.folft '^ - steveta'ffeBöcarbonylSmleol-S »
- m el ο χ den s 1 ke r be κ aard d- m el ο χ den s 1 ke r be κ aard d
OMeOMe
U'q.uí'. »'\ \\i\a '' K<Mai\n !'o e'antssd at , a\e <' \Ν -MS Λ\0'01 Hí e\<,U'q.uí '. »'\ \\ i \ a' 'K <Mai \ n!' O e'antssd at, a \ e <'\ Ν -MS Λ \ 0'01 Hí e \ <,
556,05.556.05.
KM. Példa {2-Í4'»CAa'jia«}<&iáí'6Xim1»o)íae<íl)f«BUIísrbö»ítemiaohS-meto8lfe»H}~N-(S~bféms2’·KM. Example {2-4 '»CAa'jia«} <& l''6Xim1 »o) íae <ll) f« BUIísbö »judemohS-meto8lfe» H} ~ N- (S ~ bféms2' ·
-pfridOjtorOöxdndd-pfridOjtorOöxdndd
A ekn szeriek vegyelek·:; a (85. példában leirí eljárással állítjuk ele, MS C^jH^BrNkO^ IM-ril)': 484,I like it · :; (prepared according to the procedure of Example 85, MS C 24 H 24 Br 3 O 4 O 1 H -myl) ': 484,
456,0.456.0.
IV. kiöálíkási példaARC. an example of a breakout
X($”Klór-2”pfrídili-6”(4”eksneíe»dkarboefla«iíney3-lsldrí>xdenillkafbnsa{nidX ($ 'chloro-2' pfrídili-6 "(4" eksneíe »dkarboefla« iíney3-lsldrí> xdenillkafbnsa {nid
oShe
Clcl
SOi) sag £ 1,3 Hanoi) N-<'S-ktör-2-piridil)'244-cíanofenií'karix>HilaH5Íno>5-metoxifeniikarbosarEiid 100 mi díklörmeíánnn'· kószáit szoszpenxióiáhö?. -78 °C-on 3 ml hátmibíeurndei adunk. Az elegyet környezeti hótnér'<xk <k ' U, ál -.0-. 1»\ \ s I ), χ Y » 's »íi\R t \ χ n W Ibi '1 \ '1' Uh végűi vákuumbőii szárítjuk, A színkám bepároijuk, és sí tnaradéknt etibacetátíai exirabáijuk, A szerves extrák'«'unt i-Hiírtt s ι/ex a m n m'»W id Maahd mossuk χ' » a λ x \ be$?A Mm \ \ ι xs/ueuradö szilárd ímysgot egyeMijük a szűréssel kapott szilárd snyaggak tgy-összeseit 430 mg (90 36) cirn szerinti vegySletet kapunk, Mb CjöHíjClROj. (M+.H)': 393,0.SOi) sag £ 1.3 Hanoi) N - ('S-tert-2-pyridyl)'244-cyanophenyl-carboxy>HilaH5> 5-methoxyphenylcarbosareate 100 ml of dichloromethane was observed. At -78 ° C, 3 ml of dorsal root was added. The mixture was subjected to ambient snowfall '< x k <k' U, pseudo -.0-. 1 »\ i s), χ Y» s »i \ R t \ χ n W Ibi '1 \' 1 'Uh is vacuum dried, the color is evaporated, and the residue is ethanol-exirabated, the organic extracts''' unt i-Mouse s ι / ex amn m '»W id Maahd wash χ'» λ x \ be $? The Mm \ \ ι xs / ueurad solid solid is the total amount of solid starch obtained by filtration 430 mg (90 36) (cirn). (M + .H) ': 393.0.
< Fioütiiíási pékin<Fiolylation baker
Fiiig 2-13-|N-{ 7-klór-2-ptndii)ixs5föi»H»!Í|'4-t4-riaaofenflix8 rhoeiiasnínofennsipieeiát)Fiiig 2-13- (N- (7-chloro-2-ptndii) (x5) (H)! (4-t4-thia-phenophenyl) 8).
ül mg AU 5 'U-Uxü} \ tM:m 2'giiixMM 11 iM'mnmi.k ηΐχηιΙ,ιηι'ΗηΙ-Α-ηηΙι.ηΟ,'υΗΐ',Μ'κ.'ΥΜίκΙ 03 sg (0,23 mami) eázmm-'ksrbftüát ás i tnl biuisrill'bftuttmíd Megyéhez szöbabörnersékleteu I,S t.d (0,13 uusöI) eíd-bimmieetmet axumk. Az eiegjei i mán ,u keverjük emui ?0 tnl etd-xKeiánm <-s 10 ml vizM rnaüjuk .A szerves rétegei ielíígti vizes bátrissübklöt'jd-dídartai messuk, szárítjuk ás bepárnljsik, így 70 mg nyers vegyütefeg kapunk, atnelyet további Őszi Sas nélkül használunk lek MS OUAkAOibbüs (M r 11 >' 4?9,0.yl mg AU 5 'U-Uxü} \ tM: m 2'giiixMM 11 iM'mnmi.k ηΐχηιΙ, ιηι'ΗηΙ-Α-ηηΙι.ηΟ,' υΗΐ ', Μ'κ.'ΥΜίκΙ 03 sg (0.23 mami) eázmm'ksrbftüátás and i tnl biuisrill'bftuttmíd County has a partnership with I, S td (0.13 neö) eíd-bimmieetmet axumk. The organic layers were slurried in aqueous brine, dried and evaporated to give 70 mg of crude compound without further purification. we use le MS OUAkAOibbüs (M r 11>'4? 9.0.
194, Példa194, Example
Maid (2 M i|4 Kdmíeiílzirnnolsiímnntsuntilfeíiíilkarhsíiíiiííiíísísüoj 3-|A (ü kkm-2 -píríddlkarinonMijiMioxsjaeetáí)Maid (2Mi | 4 Kmdilylsilncrmnccccccccccccccccccccccgccgccgccgccccccccccccccccccgccccc) 3 (A) (kkm-2-pyridylcarbinone)
A . eim szerinti vegyületet a i 76. páídáhaá leírt eljárással áliíbnk Mii. MS CMzAÓNÁs (MM)'; s ι ο, 1 106. Példa (2-{44Ám!no(h1drnxÍíninö)mei:il|feetsikarbóüÍÍamsü«}M-bidröxlfímiÍj-N-(S-kÍÁn-2-plMdiÓkárboxamidTHE . The compound of the present invention was prepared according to the procedure described in Example 76, Mii. MS CMSN (MM) '; EXAMPLE 106 (2- {44-Amino-(H1-Dimethoxy) -methyl) -cyclo-carboxylic acid} -M-bydroxylphenyl] -N- (S-quin-2-methyl-carboxamide)
Η ,,ΟΗ .,Ύ,Α Λ 1 IIΗ ,, ΟΗ., Ύ, Α Λ 1 II
1 ,,ΗΗ Ο1 ,, ΗΗ Ο
ÖSHE
ΟΗΟΗ
Α « ίΑ «ί
Η 'w' γ,,-Α ,bL x, ,-ϊί··χ,,, '/χχ χ,ΐΗ 'w' γ ,, - Α, bL x,, -ϊί ·· χ ,,, '/ χχ χ, ΐ
A eís« szerinti vegyületek a 183, példában lein eljárással állítják elő. MS €2ÖB^CIKA {Ms-MaV 448,0. 106. PéldaThe compounds of the above were prepared by the lein method in Example 183. MS € 2Ö B ^ CIKA {Ms-MaV 448.0. Example 106
4-(Ν' 12 4 Nn S-kkn ü'psriddiksrhasneOp 4'líHhovikadiOsrOanad5)í<-ndkatOe\45nkdsi4- (Ν '12 4 Nn S-kkn ü'ididdiksrhasneOp 4'lHhovikadiOsrOanad5) í <-ndkatOe \ 45nkdsi
QHQH
A cím szerinti vegyületek a IV. előállítási példában leírt eljárással állítják ele, .MS CjeHigCtM^O·? (MH-H)kThe title compounds are shown in Scheme IV. is prepared according to the procedure described in Production Example .MS CjeHigCtM ^ O ·? (MH-H) k
41.0,1.41.0,1.
107. PéldaExample 107
2'j4'((4'lí4Ínteldsjni»tdíniiNe.tnetiljfenii}knri>88.d&snh5ö)''3'jb'(S''kiás<(3'pi}4dd))knrbesnölljfeöösdjeeemv fcf2'j4 '((4'lí4Ínteldsjni »tdíniiNe.tnetiljfenii} knri> 88.d &snh5ö)''3'jb'(S''kiás<(3'pi} 4dd)) knrbesnölljfeöösdjeeemv fcf
NM I .A.,,,z.e »NM I .A. ,,, z.e »
Y \\ vY \\ v
Μ-χ,,χ v yΜ-χ ,, χ v y
B >í:B> í:
öShe
H , bili o | :14H, bili o | 14
V nV n
Sí:Ski:
'Cl lü '{''ν! pe a. euü'.u, zt ; s nvkrnII5 i <.s U'f ein.i Jx v! . \ u z\ Onnu H,s ,n'Cl lü'{'' ν ! Fri a. euü'.u, zt; s nvkrnII5 i <.s U'f ein.i Jx v ! . \ to \ Onnu H, s, n
-oldatot adónk. Az elegye; 1 órán át keverjük, majd RP-HPLC eijiaással tisztítják. így a eitn szerinti vegyületet »p| k M’-t ii x \eá Λ í> bxsolution. Its a mixture; After stirring for 1 hour, it is purified by RP-HPLC elution. Thus, the compound of eitn is »p | k M'-t ii x \ eá Λ í> bx
Claims (5)
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US15433299P | 1999-09-17 | 1999-09-17 | |
US60/154,332 | 1999-09-17 | ||
US18574600P | 2000-02-29 | 2000-02-29 | |
US60/185,746 | 2000-02-29 | ||
PCT/US2000/025196 WO2001019788A2 (en) | 1999-09-17 | 2000-09-15 | BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa |
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